9,325 results on '"MDM2"'
Search Results
2. Establishment and characterization of a novel MDM2/MYCN-co-amplified neuroblastoma cell line, NBN-SHIM, established from a late recurrent stage MS tumor.
- Author
-
Kato, Keisuke, Nagai, Jun-ichi, Goto, Hiroaki, Shinkai, Masato, Kitagawa, Norihiko, Toyoda, Yasunori, Nishi, Toshiji, Kigasawa, Hisato, Tanaka, Mio, Kurosawa, Kenji, Ito, Yumi, Haruta, Masayuki, Kamijo, Takehiko, Yoshimi, Ai, Tsuchida, Masahiro, Nagahara, Noriyuki, and Tanaka, Yukichi
- Subjects
CELL lines ,CELL culture ,CYCLIN-dependent kinases ,PLOIDY ,TELOMERES - Abstract
The biological heterogeneity of neuroblastoma underscores the need for an in vitro model of each molecularly defined subgroup to investigate tumorigenesis and develop targeted therapies. We have established a permanently growing cell line from a 12-year-old girl who developed a late recurrent stage MS, MDM2-amplified neuroblastoma arising in the liver and performed histological, molecular, cytogenetic, exome, and telomere analyses of the recurrent tumor and the cell line. On histology, the recurrent tumor was immunoreactive for TP53, CDKN1A, and MDM2. A molecular cytogenetic study of the recurrent tumor revealed the amplification of MDM2 but no amplification of MYCN. The established cell line, NBM-SHIM, showed amplification of both MDM2 and MYCN on double-minute chromosomes. A copy number evaluation based on exome data confirmed the finding for MYCN and MDM2 and further identified high ploidy on CDK4 and GLI2 loci in the recurrent tumor and the cell line. The telomere maintenance mechanism on the cell line is unusual in terms of the low expression of TERT despite MYCN amplification and alternative lengthening of telomeres suggested by positive value for C-circle assay and telomere contents quantitative assay. The cell line is unique because it was established from a MYCN-nonamplified, MDM2-amplified, late-relapsed stage MS neuroblastoma, and MYCN amplification was acquired during cell culture. Therefore, the cell line is a valuable tool for investigating neuroblastoma tumorigenesis and new molecular targeted therapies for disrupted ARF–TP53–MDM2 pathway and amplification of MDM2 and CDK4. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. Case report: Atypical lipomatous tumor of the thigh in a four-year-old girl.
- Author
-
Itaru Ogawa, Michiyuki Hakozaki, Yoichi Kaneuchi, Takeo Suzuki, Takuya Nikaido, Shoki Yamada, Akihito Utsumi, Osamu Hasegawa, Hideki Sano, and Yoshihiro Matsumoto
- Subjects
TUMORS in children ,FLUORESCENCE in situ hybridization ,PLEOMORPHIC adenoma ,MIDDLE-aged persons ,GENE amplification - Abstract
Atypical lipomatous tumors (ALTs) are locally aggressive adipocytic malignancies that frequently occur in middle-aged adults. We report the rare case of an ALT of the thigh that occurred in a 4-year-old girl. Since the tumor was initially diagnosed as a lipoblastoma by incisional biopsy, marginal resection was performed. Histopathological findings of the surgical specimen revealed the proliferation of mature and variously sized adipocytes, as well as ectopic ossification; these features differ from the typical findings of lipoblastoma. Immunohistochemical findings showed nuclear positivity for a murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) and negativity for pleomorphic adenoma gene 1 (PLAG1). Fluorescence in situ hybridization showed abnormal amplification of the MDM2 gene. The patient was thus finally diagnosed as having an ALT. No signs of local recurrence or metastasis were noted 1 year postoperatively. This case is instructive in the differential diagnosis of primary adipocytic tumors. Lipoblastomas are the most common adipocytic tumors in children, but if a tumor is located in the deep tissue or imaging findings are not typical, the possibility of ALT should be considered and immunohistochemistry for MDM2 and CDK4 should be added. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
4. Assessment of MDM2 Gene Locus Amplification by Fluorescence In-Situ Hybridization in Juvenile Ossifying Fibroma.
- Author
-
Alotaiby, Faraj, Alramadhan, Saja A., Fitzpatrick, Sarah G., Islam, Mohammed N., Cohen, Donald M., and Bhattacharyya, Indraneel
- Abstract
Juvenile ossifying fibroma (JOF) is an uncommon benign fibro-osseous lesion (BFOL) of the maxillofacial bones with a locally aggressive nature and a high recurrence rate. Murine Double Minute 2 (MDM2) is an oncogene located at chromosome 12 (12q13-15) that inhibits the tumor suppressor gene TP53. The presence of MDM2 gene locus amplification is a useful molecular adjunct in the evaluation of some sarcomas, including low-grade intramedullary osteosarcoma (LGIOS). JOF and LGIOS have some overlapping clinical and histopathological features. The aim of this study is to evaluate a series of JOF for the presence of MDM2 gene locus amplification using fluorescence in-situ hybridization (FISH). Materials and methods: With IRB approval, a search of the institutional files of the archives of the Oral Pathology and Surgical Pathology biopsy services at the University of Florida Health was performed. The cases were re-evaluated by an oral pathology resident, an oral and maxillofacial pathologist, and a bone and soft tissue pathologist. Cases with consensus in diagnosis were selected (n = 9) for MDM2 testing. Testing by FISH for MDM2 gene locus amplification was applied to all retrieved cases. Results: The examined cases were all negative for MDM2 gene locus amplification via FISH testing. Conclusion: In our small series, JOF did not demonstrate MDM2 gene locus abnormality, a characteristic of LGIOS. This finding suggests that JOF has a distinct underlying pathogenesis. If confirmed in a larger series, these findings may be useful in distinguishing these two entities in cases with overlapping features or when minimal biopsy material is available. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
5. Ribosomal Protein S4 X-Linked as a Novel Modulator of MDM2 Stability by Suppressing MDM2 Auto-Ubiquitination and SCF Complex-Mediated Ubiquitination.
- Author
-
Ryu, Satsuki, Nakashima, Hiroki, Tanaka, Yuka, Mukai, Risa, Ishihara, Yasuhiro, Tominaga, Takashi, and Ohshima, Takayuki
- Subjects
- *
SCAFFOLD proteins , *CELL transformation , *UBIQUITINATION , *CANCER cells , *PROTEINS - Abstract
Mouse double minute 2 (MDM2) is an oncoprotein that is frequently overexpressed in tumors and enhances cellular transformation. Owing to the important role of MDM2 in modulating p53 function, it is crucial to understand the mechanism underlying the regulation of MDM2 levels. We identified ribosomal protein S4X-linked (RPS4X) as a novel binding partner of MDM2 and showed that RPS4X promotes MDM2 stability. RPS4X suppressed polyubiquitination of MDM2 by suppressing homodimer formation and preventing auto-ubiquitination. Moreover, RPS4X inhibited the interaction between MDM2 and Cullin1, a scaffold protein of the Skp1-Cullin1-F-box protein (SCF) complex and an E3 ubiquitin ligase for MDM2. RPS4X expression in cells enhanced the steady-state level of MDM2 protein. RPS4X was associated not only with MDM2 but also with Cullin1 and then blocked the MDM2/Cullin1 interaction. This is the first report of an interaction between ribosomal proteins (RPs) and Cullin1. Our results contribute to the elucidation of the MDM2 stabilization mechanism in cancer cells, expanding our understanding of the new functions of RPs. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
6. Diagnosing liposarcoma on (peri)‐renal mass biopsy: A clinicopathological study of 30 cases.
- Author
-
Potterveld, Susan K, Mubeen, Aysha, Anderson, William J, Clay, Michael R, Bourgeau, Melanie, Charville, Gregory W, and Sangoi, Ankur R
- Subjects
- *
LIPOSARCOMA , *KIDNEY tumors , *TRANSITIONAL cell carcinoma , *RENAL cell carcinoma , *BIOPSY , *KIDNEYS - Abstract
Aims: Classification of renal neoplasms on small tissue biopsies is in increasing demand, and maintaining broad differential diagnostic considerations in this setting is necessary. When evaluating a renal or perirenal tumour biopsy with sarcomatoid morphology, together with sarcomatoid renal cell carcinoma and sarcomatoid urothelial carcinoma as top diagnostic considerations, it is vital to additionally consider the possibility of well‐differentiated and de‐differentiated liposarcoma. Methods and results: This study reports a series of 30 biopsy samples from sites in or around the kidney collected from four institutions in which the correct diagnosis was either well‐differentiated or de‐differentiated liposarcoma. The majority (26 of 30, 87%) of lesions were accurately diagnosed on biopsy sampling, all of which incorporated testing for MDM2 by immunohistochemistry (IHC), fluorescence in‐situ hybridisation (FISH) or a combination of the two as part of the diagnostic work‐up. Tumour expression of MDM2 by IHC without confirmatory FISH analysis was sometimes (30%) sufficient to reach a diagnosis, but demonstration of MDM2 amplification by FISH was ascertained in the majority (57%) of biopsy samples. A diagnosis of de‐differentiated liposarcoma was not definitively established until resection in four (13%) patients, as no MDM2 testing was performed on the corresponding pre‐operative biopsies. Conclusions: When a retroperitoneal tumour is not clinically suspected, histological consideration of a liposarcoma diagnosis may be overlooked. Implementation of ancillary immunohistochemical and cytogenetic testing can ultimately lead to a definitive diagnosis in this potentially misleading anatomical location. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
7. A Case of Dedifferentiated Liposarcoma That Contributes to Accompanying Vessels of Various Size.
- Author
-
Yamada, Yosuke, Mizoguchi, Kai, Shiba, Eisuke, Mishima, Honami, Otsuki, Shinya, Hoki, Masahito, Hirata, Masahiro, Sakamoto, Akio, Matsuda, Shuichi, Marx, Alexander, Hisaoka, Masanori, and Haga, Hironori
- Subjects
- *
SOFT tissue tumors , *STRIATED muscle , *SMOOTH muscle , *MUSCLE cells , *IN situ hybridization - Abstract
Dedifferentiated liposarcoma (DDLPS) is a non-lipogenic sarcoma, generally arising from well-differentiated liposarcoma (WDLPS), although it can develop de novo. DDLPS tumors rarely trans-differentiate into non-adipose mesenchymal tissues; however, the latter lack notable variety and mostly show striated muscle or osteogenic/chondrogenic differentiation. Here, we report a case of DDLPS that contained numerous atypical vessels. A man in his sixties presented with a large tumor in his right thigh, and the tumor was surgically resected. Microscopically, most of the tumor was WDLPS, but a minor portion showed DDLPS, consisting of high-grade spindle cells. Remarkably, the DDLPS contained vessels of various sizes with atypical cytoarchitecture, including vessels with seemingly muscular layers. Immunohistochemically, the atypical cells within the vascular wall expressed aSMA, consistent with smooth muscle cells or pericytes, whereas surrounding high-grade spindle cells only focally expressed it, and these aSMA-positive cells within the vessels exhibited MDM2 amplification by immuno-fluorescence in situ hybridization. Our results demonstrate that DDLPS can trans-differentiate into smooth muscle cells of various-sized accompanying vessels, which may support their survival and proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
8. EVA1A reverses lenvatinib resistance in hepatocellular carcinoma through regulating PI3K/AKT/p53 signaling axis.
- Author
-
Liu, Xiaokun, Gao, Xiao, Yang, Yuling, Yang, Di, Guo, Qingming, Li, Lianhui, Liu, Shunlong, Cong, Wanxin, Lu, Sen, Hou, Lin, Wang, Bin, and Li, Ning
- Subjects
INHIBITION of cellular proliferation ,CELLULAR signal transduction ,DRUG resistance ,TUMOR growth ,AUTOPHAGY ,HEPATOCELLULAR carcinoma - Abstract
Lenvatinib is a commonly used first-line drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its clinical efficacy is limited due to the drug resistance. EVA1A was a newly identified tumor suppressor, nevertheless, the impact of EVA1A on resistance to lenvatinib treatment in HCC and the potential molecular mechanisms remain unknown. In this study, the expression of EVA1A in HCC lenvatinib-resistant cells is decreased and its low expression was associated with a poor prognosis of HCC. Overexpression of EVA1A reversed lenvatinib resistance in vitro and in vivo, as demonstrated by its ability to promote cell apoptosis and inhibit cell proliferation, invasion, migration, EMT, and tumor growth. Silencing EVA1A in lenvatinib-sensitive parental HCC cells exerted the opposite effect and induced resistance to lenvatinib. Mechanistically, upregulated EVA1A inhibited the PI3K/AKT/MDM2 signaling pathway, resulting in a reduced interaction between MDM2 and p53, thereby stabilizing p53 and enhancing its antitumor activity. In addition, upregulated EVA1A suppressed the PI3K/AKT/mTOR signaling pathway and promoted autophagy, leading to the degradation of mutant p53 and attenuating its oncogenic impact. On the contrary, loss of EVA1A activated the PI3K/AKT/MDM2 signaling pathway and inhibited autophagy, promoting p53 proteasomal degradation and mutant p53 accumulation respectively. These findings establish a crucial role of EVA1A loss in driving lenvatinib resistance involving a mechanism of modulating PI3K/AKT/p53 signaling axis and suggest that upregulating EVA1A is a promising therapeutic strategy for alleviating resistance to lenvatinib, thereby improving the efficacy of HCC treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
9. Synthesis, characterization, and anti-cancer potential of novel p53-mediated Mdm2 and Pirh2 modulators: an integrated In silico and In vitro approach.
- Author
-
Niazi, Sarfaraj, Kavana, C. P., Aishwarya, H. K., Dharmashekar, Chandan, Jain, Anisha, Wani, Tanveer A., Shivamallu, Chandan, Purohit, Madhusudan N., Kollur, Shiva Prasad, Sekar, Mahendran, and Cui, Wenqiang
- Subjects
- *
LEUKEMIA , *CANCER treatment , *DRUG discovery , *SMALL molecules , *P53 antioncogene - Abstract
Introduction: Leukemia is a global health concern that requires alternative treatments due to the limitations of the FDA-approved drugs. Our focus is on p53, a crucial tumor suppressor that regulates cell division. It appears possible to stabilize p53 without causing damage to DNA by investigating dual-acting inhibitors that target both ligases. The paper aims to identify small molecule modulators of Mdm2 and Pirh2 by using 3D structural models of p53 residues and to further carry out the synthesis and evaluation of hit candidates for anti-cancer potency by in vitro and in silico studies. Methods: We synthesized structural analogues of MMs02943764 and MMs03738126 using a 4,5-(substituted) 1,2,4-triazole-3-thiols with 2-chloro N-phenylacetamide in acetone with derivatives of PAA and PCA were followed. Cytotoxicity assays, including MTT, Trypan Blue Exclusion, and MTS assays, were performed on cancer cell lines. Anti-proliferation activity was evaluated using K562 cells. Cell cycle analysis and protein expression studies of p53, Mdm2, and Pirh2 were conducted using flow cytometry. Results: As for results obtained from our previous studies MMs02943764, and MMs03738126 were selected among the best-fit hit molecules whose structural analogues were further subjected to molecular docking and dynamic simulation. Synthesized compounds exhibited potent anti-proliferative effects, with PAC showing significant cytotoxicity against leukemia cells. PAC induced cell cycle arrest and modulated p53, Mdm2, and Pirh2 protein expressions in K562 cells. Molecular docking revealed strong binding affinity of PAC to p53 protein, further confirmed by molecular dynamics simulation. Discussion: The study presents novel anticancer compounds targeting the p53 ubiquitination pathway, exemplified by PAC. Future perspectives involve further optimization and preclinical studies to validate PAC's potential as an effective anticancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
10. Insights into the Interaction Mechanisms of Peptide and Non-Peptide Inhibitors with MDM2 Using Gaussian-Accelerated Molecular Dynamics Simulations and Deep Learning.
- Author
-
Yang, Wanchun, Wang, Jian, Zhao, Lu, and Chen, Jianzhong
- Subjects
- *
GIBBS' energy diagram , *PRINCIPAL components analysis , *PEPTIDES , *BINDING energy , *MOLECULAR dynamics - Abstract
Inhibiting MDM2-p53 interaction is considered an efficient mode of cancer treatment. In our current study, Gaussian-accelerated molecular dynamics (GaMD), deep learning (DL), and binding free energy calculations were combined together to probe the binding mechanism of non-peptide inhibitors K23 and 0Y7 and peptide ones PDI6W and PDI to MDM2. The GaMD trajectory-based DL approach successfully identified significant functional domains, predominantly located at the helixes α2 and α2', as well as the β-strands and loops between α2 and α2'. The post-processing analysis of the GaMD simulations indicated that inhibitor binding highly influences the structural flexibility and collective motions of MDM2. Calculations of molecular mechanics–generalized Born surface area (MM-GBSA) and solvated interaction energy (SIE) not only suggest that the ranking of the calculated binding free energies is in agreement with that of the experimental results, but also verify that van der Walls interactions are the primary forces responsible for inhibitor–MDM2 binding. Our findings also indicate that peptide inhibitors yield more interaction contacts with MDM2 compared to non-peptide inhibitors. Principal component analysis (PCA) and free energy landscape (FEL) analysis indicated that the piperidinone inhibitor 0Y7 shows the most pronounced impact on the free energy profiles of MDM2, with the piperidinone inhibitor demonstrating higher fluctuation amplitudes along primary eigenvectors. The hot spots of MDM2 revealed by residue-based free energy estimation provide target sites for drug design toward MDM2. This study is expected to provide useful theoretical aid for the development of selective inhibitors of MDM2 family members. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
11. The Strong Activation of p53 Tumor Suppressor Drives the Synthesis of the Enigmatic Isoform of DUSP13 Protein.
- Author
-
Krześniak, Małgorzata, Łasut-Szyszka, Barbara, Będzińska, Agnieszka, Gdowicz-Kłosok, Agnieszka, and Rusin, Marek
- Subjects
GREEN fluorescent protein ,GENE expression ,DACTINOMYCIN ,CELL lines ,CANCER cells ,TUMOR suppressor proteins ,TUMOR suppressor genes - Abstract
The p53 tumor suppressor protein activates various sets of genes depending on its covalent modifications, which are controlled by the nature and intensity of cellular stress. We observed that actinomycin D and nutlin-3a (A + N) collaborate in inducing activating phosphorylation of p53. Our recent transcriptomic data demonstrated that these substances strongly synergize in the upregulation of DUSP13, a gene with an unusual pattern of expression, coding for obscure phosphatase having two isoforms, one expressed in the testes and the other in skeletal muscles. In cancer cells exposed to A + N, DUSP13 is expressed from an alternative promoter in the intron, resulting in the expression of an isoform named TMDP-L1. Luciferase reporter tests demonstrated that this promoter is activated by both endogenous and ectopically expressed p53. We demonstrated for the first time that mRNA expressed from this promoter actually produces the protein, which can be detected with Western blotting, in all examined cancer cell lines with wild-type p53 exposed to A + N. In some cell lines, it is also induced by clinically relevant camptothecin, by nutlin-3a acting alone, or by a combination of actinomycin D and other antagonists of p53-MDM2 interaction—idasanutlin or RG7112. This isoform, fused with green fluorescent protein, localizes in the perinuclear region of cells. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
12. MDM2 Is Essential to Maintain the Homeostasis of Epithelial Cells by Targeting p53
- Author
-
Su Wang, Shufen Zhong, Ying Huang, Songling Zhu, Shuangfeng Chen, Ran Wang, Sonam Wangmo, Bo Peng, Houkun Lv, Jichao Yang, Liyan Ma, Zhiyang Ling, Yaguang Zhang, Pengfei Sui, and Bing Sun
- Subjects
mdm2 ,p53 ,apoptosis ,alveolar type 2 cells ,type 2 lung inflammation ,Medicine ,Internal medicine ,RC31-1245 - Abstract
Introduction: MDM2 is known as the primary negative regulator of p53, and MDM2 promotes lung cancer fibrosis and lung injury through p53-dependent and p53-independent pathways. However, the mechanism by which MDM2 influences the pathogenesis of asthma is unknown. In this study, we investigated the function of MDM2 in lung epithelial cells in type 2 lung inflammation. Methods: We used type II alveolar epithelial cell-specific heterozygous knockout of Mdm2 mice to validate its function. Then papain-induced asthma model was established, and changes in inflammation were observed by measuring immunohistochemistry and flow cytometry analysis. Results: In this study, we knockdown the mouse Mdm2 gene in type 2 alveolar epithelial cells. We demonstrated that heterozygous Mdm2 gene-deleted mice were highly susceptible to protease allergen papain-induced pulmonary inflammation characterized by increased ILC2 numbers, IL-5 and IL-13 cytokine levels, and lung pathology. A mechanistic study showed that following the decreased expression of Mdm2 in lung epithelial cells and A549 cell line, p53 was overactivated, and the expression of its downstream genes p21, Puma, and Noxa was elevated, which resulted in apoptosis. After Mdm2 knockdown, the mRNA expression of inflammation-related gene IL-25, HMGB1, and TNF-α were increased, which further amplified the downstream ILC2 response and lung inflammation. Conclusion: These results indicate that Mdm2 maintains the homeostasis of lung epithelial cells by targeting P53 and regulates the function of lung epithelial cells under type 2 lung inflammation.
- Published
- 2024
- Full Text
- View/download PDF
13. Anticancer activity of Aucklandia costus Falc. terpenes: Targeting MDM2 protein inhibition for therapeutic advancements
- Author
-
Theresia Indah Budhy, Ira Arundina, Anis Irmawati, Sidarningsih, Meircurius Dwi Condro Surboyo, Cecillia Octavianni Raharjo, Ciptantyo Septyan Akbar, and Malika Qadira Rahmalia
- Subjects
admet ,aucklandia costus ,cancer ,docking ,mdm2 ,saussurea lappa ,Therapeutics. Pharmacology ,RM1-950 ,Pharmacy and materia medica ,RS1-441 - Abstract
Context: Protein 53 (p53) is a well-known tumor suppressor protein, while murine double minute 2 (MDM2) acts as a negative regulator of p53, leading to p53 inactivation and cancer development. Aucklandia costus Falc. or Saussurea lappa contains bioactive compounds, particularly terpenoids, known for their anticancer activity against various cancer cells. Targeting the p53-MDM2 protein interaction and inhibiting MDM2 are crucial strategies in cancer therapy. Aims: To analyze the anticancer properties of A. costus terpenes against MDM2 protein. Methods: The compounds costunolide, dehydrocostus lactone, lappadilactone, and cynaropicrin were docked with MDM2 (PDB ID: 4HG7) using AutoDockTools 1.5.6. Additionally, the physicochemical, pharmacokinetic, and toxicity properties were predicted using pkCSM. Results: Lappadilactone exhibited the highest binding energy value, surpassing both the control and the native ligand. Following lappadilactone, cynaropicrin, costunolide, and dehydrocostus lactone displayed decreasing binding energies. When assessing ADMET properties with pkCSM, all compounds exhibited good permeability, suggesting their ability to penetrate intestinal cell membranes, and showed no signs of hepatotoxicity. Conclusions: Lappadilactone emerges as a promising candidate with high intestinal absorption, distinctive distribution characteristics, and a lack of mutagenic or hepatotoxic effects.
- Published
- 2024
- Full Text
- View/download PDF
14. USP7 Inhibition Suppresses Neuroblastoma Growth via Induction of p53-Mediated Apoptosis and EZH2 and N-Myc Downregulation.
- Author
-
Le Clorennec, Christophe, Lee, Karen, Huo, Yuchen, and Zage, Peter
- Subjects
EZH2 ,MDM2 ,N-Myc ,USP7 inhibitor ,deubiquitinase ,neuroblastoma ,p53 ,ubiquitination ,Child ,Humans ,Apoptosis ,Down-Regulation ,Enhancer of Zeste Homolog 2 Protein ,N-Myc Proto-Oncogene Protein ,Neuroblastoma ,Tumor Suppressor Protein p53 ,Ubiquitin-Specific Peptidase 7 - Abstract
Neuroblastoma (NB) is a pediatric malignancy originating from neural crest cells of the sympathetic nervous system that accounts for 15% of all pediatric cancer deaths. Despite advances in treatment, high-risk NB remains difficult to cure, highlighting the need for novel therapeutic approaches. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that plays a critical role in tumor suppression and DNA repair, and USP7 overexpression has been associated with tumor aggressiveness in a variety of tumors, including NB. Therefore, USP7 is a potential therapeutic target for NB. The tumor suppressor p53 is a known target of USP7, and therefore reactivation of the p53 pathway may be an effective therapeutic strategy for NB treatment. We hypothesized that inhibition of USP7 would be effective against NB tumor growth. Using a novel USP7 inhibitor, Almac4, we have demonstrated significant antitumor activity, with significant decreases in both cell proliferation and cell viability in TP53 wild-type NB cell lines. USP7 inhibition in NB cells activated the p53 pathway via USP7 and MDM2 degradation, leading to reduced p53 ubiquitination and increased p53 expression in all sensitive NB cells. In addition, USP7 inhibition led to decreased N-myc protein levels in both MYCN-amplified and -nonamplified NB cell lines, but no correlation was observed between MYCN amplification and treatment response. USP7 inhibition induced apoptosis in all TP53 wild-type NB cell lines. USP7 inhibition also induced EZH2 ubiquitination and degradation. Lastly, the combination of USP7 and MDM2 inhibition showed enhanced efficacy. Our data suggests that USP7 inhibition may be a promising therapeutic strategy for children with high-risk and relapsed NB.
- Published
- 2023
15. Genomic Profiling of the Craniofacial Ossifying Fibroma by Next-Generation Sequencing.
- Author
-
Bahceci, Dorukhan, Grenert, James, Jordan, Richard, and Horvai, Andrew
- Subjects
AP-1 ,MDM2 ,Next-generation sequencing ,Ossifying fibroma ,Humans ,Male ,Female ,Infant ,Child ,Preschool ,Child ,Adolescent ,Young Adult ,Adult ,Middle Aged ,Fibroma ,Ossifying ,Genetic Profile ,Transcription Factor AP-1 ,Skull Neoplasms ,Bone Neoplasms ,Soft Tissue Neoplasms ,High-Throughput Nucleotide Sequencing ,Genomics - Abstract
BACKGROUND: Ossifying fibroma (OF) of the craniofacial skeleton is a fibro-osseous lesion characterized by various patterns of bone formation in a cellular fibroblastic stroma. The molecular landscape of OF remains mostly unknown. There are a few known pathogenic abnormalities in OF, including HRPT2 mutations in conventional OF and SATB2 translocations in juvenile psammomatoid OF. On the other hand, conflicting reports exist regarding MDM2 gene amplification and chromosomal copy number alterations (CNA) in OF. METHODS: Surgically removed biopsies and curettage specimens from OF patients were obtained. Clinical, radiographic, and pathologic features of tumors were reviewed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded blocks of tumor tissue. Capture-based DNA next-generation sequencing targeting the coding regions 529 cancer genes and select introns was performed. RESULTS: We identified 17 OF cases from 8 male and 8 female patients with mean age of 22 years (range 1-58 years). Nine case occurred in the gnathic bones and 8 in the extragnathic craniofacial bones. These cases included 3 juvenile psammomatoid OF, 6 conventional OF and 8 juvenile trabecular OF. Large-scale CNAs were present in 6 of 17 cases. Seven cases (41%) had focal amplifications including FOSB (n = 2, 11%), FOS (n = 4, 23%), COL1A1 (n = 4, 23%) and TBX3 (n = 5, 29%). Three cases (17%) had pathogenic CDC73 mutations. No cases showed focal MDM2 amplification. CONCLUSIONS: Here, we provided a comprehensive molecular characterization of OF that reveals a heterogeneous genetic profile with occasional large-scale CNAs (n = 6, 35%). FOS, FOSB, and TBX3 genes that regulate AP-1 transcriptional complex are frequently altered in OF (n = 7, 41%), chiefly in juvenile trabecular OF. These genes encode transcription factors that act as downstream effectors of the MAP kinase signaling pathway. MDM2 amplification is an exceedingly rare event in OF, if present at all, so identification of this event should continue to raise concern for low-grade gnathic osteosarcoma. In summary, our findings suggest that OF represents a heterogeneous group of tumors at the genetic level but dysregulation of the AP-1 pathway may play a role in pathogenesis of juvenile trabecular OF.
- Published
- 2023
16. Reciprocal regulation between RACGAP1 and AR contributes to endocrine therapy resistance in prostate cancer
- Author
-
Jiajia Wang, Hui Liu, Zeyuan Yu, Qianqian Zhou, Feifei Sun, Jingying Han, Lin Gao, Baokai Dou, Hanwen Zhang, Jiawei Fu, Wenqiao Jia, Weiwen Chen, Jing Hu, and Bo Han
- Subjects
CRPC ,Endocrine therapy resistance ,RACGAP1 ,AR ,AR-V7 ,MDM2 ,Medicine ,Cytology ,QH573-671 - Abstract
Abstract Background Endocrine resistance driven by sustained activation of androgen receptor (AR) signaling pathway in advanced prostate cancer (PCa) is fatal. Characterization of mechanisms underlying aberrant AR pathway activation to search for potential therapeutic strategy is particularly important. Rac GTPase-activating protein 1 (RACGAP1) is one of the specific GTPase-activating proteins. As a novel tumor proto-oncogene, overexpression of RACGAP1 was related to the occurrence of various tumors. Methods Bioinformatics methods were used to analyze the relationship of expression level between RACGAP1 and AR as well as AR pathway activation. qRT-PCR and western blotting assays were performed to assess the expression of AR/AR-V7 and RACGAP1 in PCa cells. Immunoprecipitation and immunofluorescence experiments were conducted to detect the interaction and co-localization between RACGAP1 and AR/AR-V7. Gain- and loss-of-function analyses were conducted to investigate the biological roles of RACGAP1 in PCa cells, using MTS and colony formation assays. In vivo experiments were conducted to evaluate the effect of RACGAP1 inhibition on the tumor growth. Results RACGAP1 was a gene activated by AR, which was markedly upregulated in PCa patients with CRPC and enzalutamide resistance. AR transcriptionally activated RACGAP1 expression by binding to its promoter region. Reciprocally, nuclear RACGAP1 bound to the N-terminal domain (NTD) of both AR and AR-V7, blocking their interaction with the E3 ubiquitin ligase MDM2. Consequently, this prevented the degradation of AR/AR-V7 in a ubiquitin-proteasome-dependent pathway. Notably, the positive feedback loop between RACGAP1 and AR/AR-V7 contributed to endocrine therapy resistance of CRPC. Combination of enzalutamide and in vivo cholesterol-conjugated RIG-I siRNA drugs targeting RACGAP1 induced potent inhibition of xenograft tumor growth of PCa. Conclusion In summary, our results reveal that reciprocal regulation between RACGAP1 and AR/AR-V7 contributes to the endocrine resistance in PCa. These findings highlight the therapeutic potential of combined RACGAP1 inhibition and enzalutamide in treatment of advanced PCa.
- Published
- 2024
- Full Text
- View/download PDF
17. BRD4 promotes gouty arthritis through MDM2-mediated PPARγ degradation and pyroptosis
- Author
-
Xiaoxia Xu and Hongbin Qiu
- Subjects
Gouty arthritis ,Pyroptosis ,BRD4 ,MDM2 ,PPARγ ,Ubiquitination ,Therapeutics. Pharmacology ,RM1-950 ,Biochemistry ,QD415-436 - Abstract
Abstract Background Gouty arthritis (GA) is characterized by monosodium urate (MSU) crystal accumulation that instigates NLRP3-mediated pyroptosis; however, the underlying regulatory mechanisms have yet to be fully elucidated. The present research endeavors to elucidate the regulatory mechanisms underpinning this MSU-induced pyroptotic cascade in GA. Methods J774 cells were exposed to lipopolysaccharide and MSU crystals to establish in vitro GA models, whereas C57BL/6 J male mice received MSU crystal injections to mimic in vivo GA conditions. Gene and protein expression levels were evaluated using real-time quantitative PCR, Western blotting, and immunohistochemical assays. Inflammatory markers were quantified via enzyme-linked immunosorbent assays. Pyroptosis was evaluated using immunofluorescence staining for caspase-1 and flow cytometry with caspase-1/propidium iodide staining. The interaction between MDM2 and PPARγ was analyzed through co-immunoprecipitation assays, whereas the interaction between BRD4 and the MDM2 promoter was examined using chromatin immunoprecipitation and dual-luciferase reporter assays. Mouse joint tissues were histopathologically evaluated using hematoxylin and eosin staining. Results In GA, PPARγ was downregulated, whereas its overexpression mitigated NLRP3 inflammasome activation and pyroptosis. MDM2, which was upregulated in GA, destabilized PPARγ through the ubiquitin–proteasome degradation pathway, whereas its silencing attenuated NLRP3 activation by elevating PPARγ levels. Concurrently, BRD4 was elevated in GA and exacerbated NLRP3 activation and pyroptosis by transcriptionally upregulating MDM2, thereby promoting PPARγ degradation. In vivo experiments showed that BRD4 silencing ameliorated GA through this MDM2–PPARγ–pyroptosis axis. Conclusion BRD4 promotes inflammation and pyroptosis in GA through MDM2-mediated PPARγ degradation, underscoring the therapeutic potential of targeting this pathway in GA management.
- Published
- 2024
- Full Text
- View/download PDF
18. Reciprocal regulation between RACGAP1 and AR contributes to endocrine therapy resistance in prostate cancer.
- Author
-
Wang, Jiajia, Liu, Hui, Yu, Zeyuan, Zhou, Qianqian, Sun, Feifei, Han, Jingying, Gao, Lin, Dou, Baokai, Zhang, Hanwen, Fu, Jiawei, Jia, Wenqiao, Chen, Weiwen, Hu, Jing, and Han, Bo
- Subjects
- *
HORMONE therapy , *GTPASE-activating protein , *PROSTATE cancer , *ANDROGEN receptors , *TUMOR growth , *PROMOTERS (Genetics) - Abstract
Background: Endocrine resistance driven by sustained activation of androgen receptor (AR) signaling pathway in advanced prostate cancer (PCa) is fatal. Characterization of mechanisms underlying aberrant AR pathway activation to search for potential therapeutic strategy is particularly important. Rac GTPase-activating protein 1 (RACGAP1) is one of the specific GTPase-activating proteins. As a novel tumor proto-oncogene, overexpression of RACGAP1 was related to the occurrence of various tumors. Methods: Bioinformatics methods were used to analyze the relationship of expression level between RACGAP1 and AR as well as AR pathway activation. qRT-PCR and western blotting assays were performed to assess the expression of AR/AR-V7 and RACGAP1 in PCa cells. Immunoprecipitation and immunofluorescence experiments were conducted to detect the interaction and co-localization between RACGAP1 and AR/AR-V7. Gain- and loss-of-function analyses were conducted to investigate the biological roles of RACGAP1 in PCa cells, using MTS and colony formation assays. In vivo experiments were conducted to evaluate the effect of RACGAP1 inhibition on the tumor growth. Results: RACGAP1 was a gene activated by AR, which was markedly upregulated in PCa patients with CRPC and enzalutamide resistance. AR transcriptionally activated RACGAP1 expression by binding to its promoter region. Reciprocally, nuclear RACGAP1 bound to the N-terminal domain (NTD) of both AR and AR-V7, blocking their interaction with the E3 ubiquitin ligase MDM2. Consequently, this prevented the degradation of AR/AR-V7 in a ubiquitin-proteasome-dependent pathway. Notably, the positive feedback loop between RACGAP1 and AR/AR-V7 contributed to endocrine therapy resistance of CRPC. Combination of enzalutamide and in vivo cholesterol-conjugated RIG-I siRNA drugs targeting RACGAP1 induced potent inhibition of xenograft tumor growth of PCa. Conclusion: In summary, our results reveal that reciprocal regulation between RACGAP1 and AR/AR-V7 contributes to the endocrine resistance in PCa. These findings highlight the therapeutic potential of combined RACGAP1 inhibition and enzalutamide in treatment of advanced PCa. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
19. Study on the design, synthesis, and activity of anti-tumor staple peptides targeting MDM2/MDMX.
- Author
-
Yang, Jian, Liao, Xiufei, Hu, Damin, Mo, Jinqiu, Gao, Xiurong, Liao, Hongli, Ibrahim, Eslam Ali, and Tokala, Ramya
- Subjects
- *
PEPTIDES , *TUMORS , *CANCER chemotherapy , *DNA damage , *CANCER treatment - Abstract
Staple peptides, which have a significantly enhanced pharmacological profile, are promising therapeutic molecules due to their remarkable resistance to proteolysis and cell-penetrating properties. In this study, we designed and synthesized a series of PMI-M3-based dual-targeting MDM2/MDMX staple peptides and compared them with straight-chain peptides. The staple peptide SM3-4 screened in the study induced apoptosis of tumor cells in vitro at low ^M concentrations, and the helix was significantly increased. Studies have shown that the enhancement of staple activity is related to the increase in helicity, and SM3-4 provides an effective research basis for dual-targeted anti-tumor staple peptides. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
20. Understanding the complexity of p53 in a new era of tumor suppression.
- Author
-
Liu, Yanqing, Su, Zhenyi, Tavana, Omid, and Gu, Wei
- Subjects
- *
P53 antioncogene , *TRANSCRIPTION factors , *POST-translational modification , *TUMOR growth , *ANTINEOPLASTIC agents , *CARRIER proteins - Abstract
p53 was discovered 45 years ago as an SV40 large T antigen binding protein, coded by the most frequently mutated TP53 gene in human cancers. As a transcription factor, p53 is tightly regulated by a rich network of post-translational modifications to execute its diverse functions in tumor suppression. Although early studies established p53-mediated cell-cycle arrest, apoptosis, and senescence as the classic barriers in cancer development, a growing number of new functions of p53 have been discovered and the scope of p53-mediated anti-tumor activity is largely expanded. Here, we review the complexity of different layers of p53 regulation, and the recent advance of the p53 pathway in metabolism, ferroptosis, immunity, and others that contribute to tumor suppression. We also discuss the challenge regarding how to activate p53 function specifically effective in inhibiting tumor growth without harming normal homeostasis for cancer therapy. p53 plays a central role in suppressing tumorigenesis. In this issue, Liu et al. review the complexity of different layers of p53 regulation, and the recent advance of the p53 pathway in metabolism, ferroptosis, immunity, and others that largely expand the scope of its anti-tumor activity. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
21. Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions.
- Author
-
Cordani, Marco, Garufi, Alessia, Benedetti, Rossella, Tafani, Marco, Aventaggiato, Michele, D'Orazi, Gabriella, and Cirone, Mara
- Subjects
- *
P53 antioncogene , *MUTANT proteins , *ONCOGENIC proteins , *P53 protein , *GENE regulatory networks , *PROTEOLYSIS , *HEAT shock proteins - Abstract
The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment. Despite recent progress in understanding the complexity of mutp53 in neoplastic development, the exact mechanisms of how mutp53 contributes to cancer development and how they escape proteasomal and lysosomal degradation remain only partially understood. In this review, we address recent findings in the field of oncogenic functions of mutp53 specifically regarding, but not limited to, its implications in metabolic pathways, the secretome of cancer cells, the cancer microenvironment, and the regulating scenarios of the aberrant proteasomal degradation. By analyzing proteasomal and lysosomal protein degradation, as well as its connection with autophagy, we propose new therapeutical approaches that aim to destabilize mutp53 proteins and deactivate its oncogenic functions, thereby providing a fundamental basis for further investigation and rational treatment approaches for TP53-mutated cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
22. "The 10th International MDM2 Workshop": Opening up new avenues for MDM2 and p53 research, the First International MDM2 Workshop in Asia.
- Author
-
Ohki, Rieko, Itahana, Koji, and Iwakuma, Tomoo
- Subjects
- *
DRUG discovery , *POSTER presentations , *CANCER research , *RESEARCH institutes - Abstract
The 10th International MDM2 Workshop was held at the National Cancer Center Research Institute (NCCRI) in Tokyo, Japan, from October 15 to 18, 2023. It attracted 166 participants from 12 countries. The meeting featured 52 talks and 41 poster presentations. In the first special session, six invited speakers gave educational and outstanding talks on breakthroughs in MDM2 research. Three keynote speakers presented emerging p53‐independent functions of MDM2/MDM4, functional association of MDM2/p53 with cancer immunity, and drug discovery targeting the MDM2/MDM4‐p53 pathway. Additionally, 19 invited speakers introduced their new findings. Twenty‐one presenters, many of whom were young investigators, postdocs, and students, were selected from submitted abstracts and reported their exciting and unpublished results. For poster presenters, outstanding poster awards were given to the best presenters. There were many inspiring questions and discussions throughout the meeting. Social events like a welcome party, a workshop dinner, and an optional tour enabled further scientific interactions among the participants. The meeting successfully provided an exciting platform for scientific exchange. The experience gained from organizing this meeting will be handed over to the next organizers of the 11th International MDM2 Workshop. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
23. p53/MDM2 signaling pathway in aging, senescence and tumorigenesis.
- Author
-
Huang, Youyi, Che, Xiaofang, Wang, Peter W., and Qu, Xiujuan
- Subjects
- *
IMMUNOSENESCENCE , *AGING , *CELLULAR signal transduction , *NEOPLASTIC cell transformation , *AGE factors in disease , *DNA repair - Abstract
A wealth of evidence has emerged that there is an association between aging, senescence and tumorigenesis. Senescence, a biological process by which cells cease to divide and enter a status of permanent cell cycle arrest, contributes to aging and aging-related diseases, including cancer. Aging populations have the higher incidence of cancer due to a lifetime of exposure to cancer-causing agents, reduction of repairing DNA damage, accumulated genetic mutations, and decreased immune system efficiency. Cancer patients undergoing cytotoxic therapies, such as chemotherapy and radiotherapy, accelerate aging. There is growing evidence that p53/MDM2 (murine double minute 2) axis is critically involved in regulation of aging, senescence and oncogenesis. Therefore, in this review, we describe the functions and mechanisms of p53/MDM2-mediated senescence, aging and carcinogenesis. Moreover, we highlight the small molecular inhibitors, natural compounds and PROTACs (proteolysis targeting chimeras) that target p53/MDM2 pathway to influence aging and cancer. Modification of p53/MDM2 could be a potential strategy for treatment of aging, senescence and tumorigenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
24. Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced biliary tract cancer, pancreatic ductal adenocarcinoma or other solid tumors.
- Author
-
Yoo, Changhoon, Lamarca, Angela, Choi, Hye Jin, Vogel, Arndt, Pishvaian, Michael J, Goyal, Lipika, Ueno, Makoto, Märten, Angela, Teufel, Michael, Geng, Lijiang, and Morizane, Chigusa
- Abstract
Mouse double minute 2 homolog (MDM2) is a key negative regulator of the tumor suppressor p53. Blocking the MDM2–p53 interaction, and restoring p53 function, is therefore a potential therapeutic strategy in MDM2-amplified, TP53 wild-type tumors. MDM2 is amplified in several tumor types, including biliary tract cancer (BTC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinoma and bladder cancer, all of which have limited treatment options and poor patient outcomes. Brigimadlin (BI 907828) is a highly potent MDM2–p53 antagonist that has shown promising activity in preclinical and early-phase clinical studies. This manuscript describes the rationale and design of an ongoing phase IIa/IIb Brightline-2 trial evaluating brigimadlin as second-line treatment for patients with advanced/metastatic BTC, PDAC, lung adenocarcinoma, or bladder cancer. Plain language summary Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced BTC, PDAC, or other solid tumors In some types of cancer, including cancers of the bile duct, pancreas, bladder and lung, the number of copies of a gene called MDM2 is abnormally increased (MDM2 amplification). MDM2 usually regulates p53, a protein that stops cancer cells from growing uncontrollably. When MDM2 is amplified, the cell makes too much of the MDM2 protein, which prevents p53 from stopping cancer growth. Blocking the interaction between MDM2 and p53 may allow p53 to do its job again and stop cancer cells from growing. Brightline-2 is a clinical trial that is currently in progress. This trial is assessing the efficacy and safety of an investigational drug, brigimadlin (or BI 907828), in patients with selected advanced or metastatic cancers. To be included, patients must have advanced biliary tract cancer, pancreatic ductal adenocarcinoma, bladder cancer, or lung adenocarcinoma. The tumor must show amplification of MDM2 when tested by a laboratory. Patients will take a 45 mg tablet of brigimadlin by mouth, once every 3 weeks. In this trial, researchers are investigating the ability of the drug to shrink tumors, the side effects of the drug, and the impact of the drug on a patients' quality of life. The goal of this trial is to assess the potential of brigimadlin as a new treatment option for patients with advanced biliary tract cancer, pancreatic ductal adenocarcinoma, bladder cancer, or lung adenocarcinoma. Clinical Trial Registration:NCT05512377 (ClinicalTrials.gov) Executive summary Background Patients with advanced or metastatic biliary tract cancer (BTC) or pancreatic ductal adenocarcinoma (PDAC) generally have a poor prognosis, with a median survival of ≈1 year. Patients with lung adenocarcinomas or bladder cancer have similarly poor survival rates. Current first- and second-line treatments for these conditions include chemotherapy; however, the benefit – especially for second-line chemotherapy – is modest. The MDM2 gene encodes a negative regulator of the p53 tumor suppressor protein. Antagonism of Mouse double minute 2 homolog (MDM2) can restore p53 activity and represents a novel therapeutic strategy. MDM2 is amplified in various solid tumors, including BTC (5–8%), PDAC (1%), lung adenocarcinoma (5%) and bladder cancer (8%). Brigimadlin (BI 907828) Brigimadlin (or BI 907828) is an oral, MDM2–p53 antagonist that inhibits the interaction between MDM2 and p53. In a subgroup of ten patients with advanced MDM2-amplified BTC from two ongoing phase Ia/Ib trials, brigimadlin (with or without the anti-PD-1 inhibitor ezabenlimab) showed early signs of activity, with 50% of patients demonstrating a partial response. In these two phase Ia/Ib trials, brigimadlin was associated with a manageable safety profile, both as monotherapy and in combination with ezabenlimab. Brightline-2 trial This is an ongoing phase IIa/IIb, open-label, single-arm, multicenter trial with brigimadlin in patients with BTC, PDAC, or other solid tumors. Eligible patients are adults with locally advanced or metastatic MDM2-amplified, TP53 wild-type BTC, PDAC, lung adenocarcinoma, or bladder cancer with at least one measurable target lesion, Eastern Cooperative Oncology Group performance status of 0 or 1, and who have received appropriate prior standard of care therapy. The phase IIa part of the trial will include five cohorts with the following estimated patient numbers: Cohort 1 (BTC; n = 30), Cohort 1-CN (BTC in mainland China; n = 25), Cohort 2 (PDAC; n = 10), Cohort 3 (lung adenocarcinoma; n = 15) and Cohort 4 (bladder cancer; n = 15). All patients will receive brigimadlin 45 mg orally once every 3 weeks, with up to two dose reductions allowed. An interim futility analysis will be performed for the first 30 patients in Cohort 1 only. A non-binding futility boundary of objective response rate = 20% is planned for the interim futility analysis. The total sample size for Cohort 1 will be ∼90 patients. The primary end point is objective response rate based on central independent review. Secondary end points include duration of response, progression-free survival, overall survival, disease control, patient-reported outcomes, treatment-emergent adverse events and the occurrence of treatment-emergent adverse events leading to discontinuation of brigimadlin. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
25. BRD4 promotes gouty arthritis through MDM2-mediated PPARγ degradation and pyroptosis.
- Author
-
Xu, Xiaoxia and Qiu, Hongbin
- Subjects
- *
PYROPTOSIS , *HEMATOXYLIN & eosin staining , *ENZYME-linked immunosorbent assay , *ARTHRITIS - Abstract
Background: Gouty arthritis (GA) is characterized by monosodium urate (MSU) crystal accumulation that instigates NLRP3-mediated pyroptosis; however, the underlying regulatory mechanisms have yet to be fully elucidated. The present research endeavors to elucidate the regulatory mechanisms underpinning this MSU-induced pyroptotic cascade in GA. Methods: J774 cells were exposed to lipopolysaccharide and MSU crystals to establish in vitro GA models, whereas C57BL/6 J male mice received MSU crystal injections to mimic in vivo GA conditions. Gene and protein expression levels were evaluated using real-time quantitative PCR, Western blotting, and immunohistochemical assays. Inflammatory markers were quantified via enzyme-linked immunosorbent assays. Pyroptosis was evaluated using immunofluorescence staining for caspase-1 and flow cytometry with caspase-1/propidium iodide staining. The interaction between MDM2 and PPARγ was analyzed through co-immunoprecipitation assays, whereas the interaction between BRD4 and the MDM2 promoter was examined using chromatin immunoprecipitation and dual-luciferase reporter assays. Mouse joint tissues were histopathologically evaluated using hematoxylin and eosin staining. Results: In GA, PPARγ was downregulated, whereas its overexpression mitigated NLRP3 inflammasome activation and pyroptosis. MDM2, which was upregulated in GA, destabilized PPARγ through the ubiquitin–proteasome degradation pathway, whereas its silencing attenuated NLRP3 activation by elevating PPARγ levels. Concurrently, BRD4 was elevated in GA and exacerbated NLRP3 activation and pyroptosis by transcriptionally upregulating MDM2, thereby promoting PPARγ degradation. In vivo experiments showed that BRD4 silencing ameliorated GA through this MDM2–PPARγ–pyroptosis axis. Conclusion: BRD4 promotes inflammation and pyroptosis in GA through MDM2-mediated PPARγ degradation, underscoring the therapeutic potential of targeting this pathway in GA management. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
26. Primary Cardiac Intimal Sarcoma: Multi-Layered Strategy and Core Role of MDM2 Amplification/Co-Amplification and MDM2 Immunostaining.
- Author
-
Nistor, Claudiu, Carsote, Mara, Cucu, Anca-Pati, Stanciu, Mihaela, Popa, Florina Ligia, Ciuche, Adrian, and Ciobica, Mihai-Lucian
- Subjects
- *
HEART failure , *RIGHT heart atrium , *HEART tumors , *SYMPTOMS , *IMMUNOSTAINING , *PROGNOSIS , *MYOCARDIAL infarction - Abstract
Primary cardiac tumours are relatively uncommon (75% are benign). Across the other 25%, representing malignant neoplasia, sarcomas account for 75–95%, and primary cardiac intimal sarcoma (PCIS) is one of the rarest findings. We aimed to present a comprehensive review and practical considerations from a multidisciplinary perspective with regard to the most recent published data in the specific domain of PCIS. We covered the issues of awareness amid daily practice clinical presentation to ultra-qualified management in order to achieve an adequate diagnosis and prompt intervention, also emphasizing the core role of MDM2 immunostaining and MDM2 genetic analysis. An additional base for practical points was provided by a novel on-point clinical vignette with MDM2-positive status. According to our methods (PubMed database search of full-length, English publications from January 2021 to March 2023), we identified three studies and 23 single case reports represented by 22 adults (male-to-female ratio of 1.2; male population with an average age of 53.75 years, range: 35–81; woman mean age of 55.5 years, range: 34–70) and a 4-year-old child. The tumour-related clinical picture was recognized in a matter of one day to ten months on first admission. These non-specific data (with a very low index of suspicion) included heart failure at least NYHA class II, mitral regurgitation and pulmonary hypertension, acute myocardial infarction, ischemic stroke, obstructive shock, and paroxysmal atrial fibrillation. Awareness might come from other complaints such as (most common) dyspnoea, palpitation, chest pressure, cough, asthenia, sudden fatigue, weakness, malaise, anorexia, weight loss, headache, hyperhidrosis, night sweats, and epigastric pain. Two individuals were initially misdiagnosed as having endocarditis. A history of prior treated non-cardiac malignancy was registered in 3/23 subjects. Distant metastasis as the first step of detection (n = 2/23; specifically, brain and intestinal) or during follow-up (n = 6/23; namely, intestinal, brain and bone, in two cases for each, and adrenal) required additional imagery tools (26% of the patients had distant metastasis). Transoesophageal echocardiography, computed tomography (CT), magnetic resonance imagery, and even 18F-FDG positronic emission tomography-CT (which shows hypermetabolic lesions in PCIS) represent the basis of multimodal tools of investigation. Tumour size varied from 3 cm to ≥9 cm (average largest diameter of 5.5 cm). The most frequent sites were the left atrium followed by the right ventricle and the right atrium. Post-operatory histological confirmation was provided in 20/23 cases and, upon tumour biopsy, in 3/23 of them. The post-surgery maximum free-disease interval was 8 years, the fatal outcome was at the earliest two weeks since initial admission. MDM2 analysis was provided in 7/23 subjects in terms of MDM2-positive status (two out of three subjects) at immunohistochemistry and MDM2 amplification (four out of five subjects) at genetic analysis. Additionally, another three studies addressed PCISs, and two of them offered specific MDM2/MDM2 assays (n = 35 patients with PCISs); among the provided data, we mention that one cohort (n = 20) identified a rate of 55% with regard to MDM2 amplification in intimal sarcomas, and this correlated with a myxoid pattern; another cohort (n = 15) showed that MDM2-positive had a better prognostic than MDM2-negative immunostaining. To summarize, MDM2 amplification and co-amplification, for example, with MDM4, CDK4, HMGA3, CCND3, PDGFRA, TERT, KIT, CCND3, and HDAC9, might improve the diagnosis of PCIS in addition to MDM2 immunostaining since 10–20% of these tumours are MDM2-negative. Further studies are necessary to highlight MDM2 applicability as a prognostic factor and as an element to be taken into account amid multi-layered management in an otherwise very aggressive malignancy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
27. Telengiectatic osteosarcoma of mandible with special emphasis on immunohistochemical and molecular characteristics: A case report with review of literature.
- Author
-
Khan, Eram, Verma, Saloni, Sivakumar, N., Sharma, Pooja, Chandra, Shaleen, and Gupta, Shalini
- Subjects
LITERATURE reviews ,ANEURYSMAL bone cyst ,IN situ hybridization ,CAVERNOUS hemangioma ,OSTEOSARCOMA ,BONE cysts ,MANDIBLE - Abstract
Background: Telangiectatic osteosarcoma (TOS) is an uncommon pathology accounting for about 0.4%–12% of all osteosarcomas with predilection for younger adults. It is most frequently seen in the metaphysis of long bones, appearing as painful osteolytic mass that histopathologically characterized by dilated, blood‐filled vascular spaces lined by malignant osteoblasts along with osteoid formation. It has exchangeable clinical, radiological and pathological features with benign lesions like aneurysmal bone cyst and giant cell tumour of bone as well. Thus, delineating this malignancy from its benign counterparts is a crucial part in the therapeutic management. Aim: To report a case of telengiectatic osteosarcoma of jaw in a 17 year old female patient with special highlights on molecular diagnostics and therapeutic modules. Materials and Methods: A panel of immunohistochemical markers comprising of SATB2, CDK4, MDM2, panCK, CD31, desmin, NKX2.2 and TLE1 were employed in combination with fluorescent in‐situ hybridization to detect the prevalence of rearrangement in CDK4 and MDM2 genes. Results: On immunohistochemistry, the neoplastic cells were strongly positive for SATB2 and negative for CDK4, MDM2, panCK, CD31, desmin, NKX2.2 and TLE1. Fluorescent in‐situ hybridization of CDK4 and MDM2 genes was also negative. Conclusion: Considering its rarity in jaws combined with clinicopathological overlap with other benign pathologies, diagnosis of this entity is crucial in treatment planning and prognostic significance. Moreover, only five cases of TOS have been reported so far in the craniofacial region. Here, we have reported the sixth case of its kind with detailed clarification pertaining to its immunohistochemical and molecular aspects. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
28. N6 methyladenosine eraser FTO suppresses Staphylococcus aureus‐induced ferroptosis of bone marrow mesenchymal stem cells to ameliorate osteomyelitis through regulating the MDM2/TLR4/SLC7A11 signaling pathway.
- Author
-
Song, Muguo, Lv, Kehan, Xu, Zhi, Li, Junyi, Sun, Jian, Shi, Jian, and Xu, Yongqing
- Subjects
- *
MESENCHYMAL stem cells , *BONE marrow , *OSTEOMYELITIS , *CELLULAR signal transduction , *STAPHYLOCOCCUS , *PLURIPOTENT stem cells - Abstract
Osteomyelitis is a bone destructive inflammatory disease caused by infection. Ferroptosis is closely related to multiple inflammatory diseases, but the role of ferroptosis in Staphylococcus aureus (SA)‐induced osteomyelitis remains unknown. In the present study, we found that SA treatment promoted the accumulation of iron, Fe2+, lipid peroxide, and malondialdehyde, increased TFRC and reduced FTH1 and GPX4 to trigger ferroptosis in rat bone marrow mesenchymal stem cells (BMSCs). Interestingly, increased level of N6 methyl adenosine (m6A) modification along with decreased expression level of m6A eraser FTO were observed in SA‐induced BMSCs, while upregulating FTO alleviated SA‐triggered ferroptosis and protected cell viability in BMSCs. Mechanistically, MDM2 was identified as a target of FTO‐mediated m6A demethylation, and FTO upregulation promoted MDM2 instability to downregulated TLR4 signal and elevate the expression of SLC7A11 and GPX4 in SA‐induced BMSCs. Functional recovery experiments verified that overexpressing MDM2 or TLR4 reversed the inhibiting effect of FTO upregulation on ferroptosis in SA‐treated BMSCs. Additionally, FTO upregulation restrained ferroptosis and pathological damage to bone tissue in SA‐induced osteomyelitis model rats. Altogether, m6A eraser FTO alleviates SA‐induced ferroptosis in osteomyelitis models partly through inhibiting the MDM2‐TLR4 axis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
29. Synthesis, characterization, and anti-cancer potential of novel p53-mediated Mdm2 and Pirh2 modulators: an integrated In silico and In vitro approach
- Author
-
Sarfaraj Niazi, C. P. Kavana, H. K. Aishwarya, Chandan Dharmashekar, Anisha Jain, Tanveer A. Wani, Chandan Shivamallu, Madhusudan N. Purohit, and Shiva Prasad Kollur
- Subjects
leukemia ,MDM2 ,p53 ,cancer therapy ,drug discovery ,small molecule modulators ,Chemistry ,QD1-999 - Abstract
Introduction: Leukemia is a global health concern that requires alternative treatments due to the limitations of the FDA-approved drugs. Our focus is on p53, a crucial tumor suppressor that regulates cell division. It appears possible to stabilize p53 without causing damage to DNA by investigating dual-acting inhibitors that target both ligases. The paper aims to identify small molecule modulators of Mdm2 and Pirh2 by using 3D structural models of p53 residues and to further carry out the synthesis and evaluation of hit candidates for anti-cancer potency by in vitro and in silico studies.Methods: We synthesized structural analogues of MMs02943764 and MMs03738126 using a 4,5-(substituted) 1,2,4-triazole-3-thiols with 2-chloro N-phenylacetamide in acetone with derivatives of PAA and PCA were followed. Cytotoxicity assays, including MTT, Trypan Blue Exclusion, and MTS assays, were performed on cancer cell lines. Anti-proliferation activity was evaluated using K562 cells. Cell cycle analysis and protein expression studies of p53, Mdm2, and Pirh2 were conducted using flow cytometry.Results: As for results obtained from our previous studies MMs02943764, and MMs03738126 were selected among the best-fit hit molecules whose structural analogues were further subjected to molecular docking and dynamic simulation. Synthesized compounds exhibited potent anti-proliferative effects, with PAC showing significant cytotoxicity against leukemia cells. PAC induced cell cycle arrest and modulated p53, Mdm2, and Pirh2 protein expressions in K562 cells. Molecular docking revealed strong binding affinity of PAC to p53 protein, further confirmed by molecular dynamics simulation.Discussion: The study presents novel anticancer compounds targeting the p53 ubiquitination pathway, exemplified by PAC. Future perspectives involve further optimization and preclinical studies to validate PAC’s potential as an effective anticancer therapy.
- Published
- 2024
- Full Text
- View/download PDF
30. Characterisation of ZFP36L1, a novel breast cancer predisposition gene
- Author
-
Winter, Timothy, Orr, Nicholas, and Jafarnejad Shourkaei, Seyed Mehdi
- Subjects
ZFP36L1 ,breast cancer ,post-GWAS ,GWAS ,functional genomics ,RNA binding protein ,DNA damage ,proliferation ,MDM2 ,14q24.1 - Abstract
Genetic susceptibility is a well-established risk factor for breast cancer. Several high and moderate penetrance predisposition genes have been identified to date including BRCA1, BRCA2, CHEK2, ATM, and PALB2. Mutations in any of these genes result in greater than two-fold increases in risk of breast cancer formation to an individual but, owing to their rarity within the population, they are predicted to account for less than 25% of the familial risk of breast cancer. It is now thought that the remaining genetic risk is attributable not to rare, high penetrance mutations but to more common single nucleotide polymorphisms (SNPs) with comparatively modest individual effect sizes. The dawn of genome wide association studies (GWAS) has resulted in an enormous wave of discovery of approximately 200 of these SNPs. However, the majority are found in non-coding DNA and so the functional causes underpinning their risk effects are mostly unknown. Recent work from our lab and others has demonstrated by capture Hi-C that one such risk locus, 14q24.1, interacts with the promoter of a nearby RNA binding protein encoding gene, ZFP36L1. Expression quantitative trait locus (eQTL) analysis using TCGA data revealed a statistically significant reduction in ZFP36L1 expression (P = 0.003) in carriers of the risk allele of the lead SNP at this region. These findings suggest that one or more functional SNPs at 14q24.1 influence breast cancer risk by repressing the expression of ZFP36L1. The work presented in this thesis illuminates the impact of abrogated ZFP36L1 expression in non-cancerous human breast epithelial cells and proposes mechanisms by which this affects cancer risk. Using a profile of assays examining various hallmarks of cancer, this work identifies two novel cancer-relevant cellular processes impacted by loss of ZFP36L1, as well as one novel functional mechanism of action of ZFP36L1, and two critical cancer-relevant mRNA targets of repression by ZFP36L1.
- Published
- 2023
31. E3 Ubiquitin Ligases and Their Therapeutic Applications in Cancers: Narrative Review.
- Author
-
Jamal, Azfar
- Subjects
- *
LIGASES , *UBIQUITIN , *BIOCHEMICAL substrates , *ENZYMES , *MOLECULES , *UBIQUITIN ligases - Abstract
E3 ubiquitin ligases are a class of enzymes, essential for maintaining the equilibrium of cells by binding ubiquitin molecules to substrates to mark them for destruction. Since many cancer‑related proteins, including both oncogenic and tumor‑suppressive ones, are controlled by the ubiquitin‑proteasome system, E3 ligases have drawn a great deal of interest as potential targets for the creation of anti‑cancer drugs. This is because E3 ligases function as modules that select the substrates that are intended for degradation, giving them the ability to particularly affect proteins that are connected to cancer. Their molecular properties and the ways in which they work serve as the basis for these distinctions. Investment in the creation of bioactive substances that can target E3 ligases is essential given the crucial roles they play in cancer. These substances have the potential to be powerful cancer‑fighting tools. In this review, we explore the crucial roles that E3 ligases play in the biology of cancer. We also examine the current bioactive substances that have been created to target different E3 ligases, emphasizing their potential as candidates for treating the cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
32. Sex-Specific Associations of MDM2 and MDM4 Variants with Risk of Multiple Primary Melanomas and Melanoma Survival in Non-Hispanic Whites
- Author
-
Ward, Sarah V, Autuori, Isidora, Luo, Li, LaPilla, Emily, Yoo, Sarah, Sharma, Ajay, Busam, Klaus J, Olilla, David W, Dwyer, Terence, Anton-Culver, Hoda, Zanetti, Roberto, Sacchetto, Lidia, Cust, Anne E, Gallagher, Richard P, Kanetsky, Peter A, Rosso, Stefano, Begg, Colin B, Berwick, Marianne, Thomas, Nancy E, and Orlow, Irene
- Subjects
Genetics ,Cancer ,Prevention ,MDM2 ,MDM4 ,melanoma ,gene ,polymorphism ,risk ,survival ,sex ,functional ,estrogen-receptor ,GEM Study Group ,Oncology and Carcinogenesis - Abstract
MDM2-SNP309 (rs2279744), a common genetic modifier of cancer incidence in Li-Fraumeni syndrome, modifies risk, age of onset, or prognosis in a variety of cancers. Melanoma incidence and outcomes vary by sex, and although SNP309 exerts an effect on the estrogen receptor, no consensus exists on its effect on melanoma. MDM2 and MDM4 restrain p53-mediated tumor suppression, independently or together. We investigated SNP309, an a priori MDM4-rs4245739, and two coinherited variants, in a population-based cohort of 3663 primary incident melanomas. Per-allele and per-haplotype (MDM2_SNP309-SNP285; MDM4_rs4245739-rs1563828) odds ratios (OR) for multiple-melanoma were estimated with logistic regression models. Hazard ratios (HR) for melanoma death were estimated with Cox proportional hazards models. In analyses adjusted for covariates, females carrying MDM4-rs4245739*C were more likely to develop multiple melanomas (ORper-allele = 1.25, 95% CI 1.03-1.51, and Ptrend = 0.03), while MDM2-rs2279744*G was inversely associated with melanoma-death (HRper-allele = 0.63, 95% CI 0.42-0.95, and Ptrend = 0.03). We identified 16 coinherited expression quantitative loci that control the expression of MDM2, MDM4, and other genes in the skin, brain, and lungs. Our results suggest that MDM4/MDM2 variants are associated with the development of subsequent primaries and with the death of melanoma in a sex-dependent manner. Further investigations of the complex MDM2/MDM4 motif, and its contribution to the tumor microenvironment and observed associations, are warranted.
- Published
- 2023
33. BH3-mimetics or DNA-damaging agents in combination with RG7388 overcome p53 mutation-induced resistance to MDM2 inhibition
- Author
-
Pervushin, N. V., Nilov, D. K., Pushkarev, S. V., Shipunova, V. O., Badlaeva, A. S., Yapryntseva, M. A., Kopytova, D. V., Zhivotovsky, B., and Kopeina, G. S.
- Published
- 2024
- Full Text
- View/download PDF
34. Strong activation of p53 by actinomycin D and nutlin-3a overcomes the resistance of cancer cells to the pro-apoptotic activity of the FAS ligand
- Author
-
Łasut-Szyszka, Barbara, Gdowicz-Kłosok, Agnieszka, Krześniak, Małgorzata, Głowala-Kosińska, Magdalena, Będzińska, Agnieszka, and Rusin, Marek
- Published
- 2024
- Full Text
- View/download PDF
35. p53 biology and reactivation for improved therapy in MDS and AML
- Author
-
Joanna E. Zawacka
- Subjects
MDS ,AML ,p53 ,MDM2 ,MDM4 ,p73 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) originate from preleukemic hematopoietic conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS) and have variable outcomes despite the successful implementation of targeted therapies. The prognosis differs depending on the molecular subgroup. In patients with TP53 mutations, the most inferior outcomes across independent studies were observed. Myeloid malignancies with TP53 mutations have complex cytogenetics and extensive structural variants. These factors contribute to worse responses to induction therapy, demethylating agents, or venetoclax-based treatments. Survival of patients with biallelic TP53 gene mutations is often less than one year but this depends on the type of treatment applied. It is still controversial whether the allelic state of mutant TP53 impacts the outcomes in patients with AML and high-risk MDS. Further studies are needed to justify estimating TP53 LOH status for better risk assessment. Yet, TP53-mutated MDS, MDS/AML and AML are now classified separately in the International Consensus Classification (ICC). In the clinical setting, the wild-type p53 protein is reactivated pharmacologically by targeting p53/MDM2/MDM4 interactions and mutant p53 reactivation is achieved by refolding the DNA binding domain to wild-type-like conformation or via targeted degradation of the mutated protein. This review discusses our current understanding of p53 biology in MDS and AML and the promises and failures of wild-type and mutant p53 reactivation in the clinical trial setting.
- Published
- 2024
- Full Text
- View/download PDF
36. Genome-wide CRISPR screen identifies ESPL1 limits the response of gastric cancer cells to apatinib
- Author
-
Bei Zhang, Yan Chen, Xinqi Chen, Zhiyao Ren, Hong Xiang, Lipeng Mao, and Guodong Zhu
- Subjects
Apatinib resistance ,ESPL1 ,CRISPR screening ,MDM2 ,Gastric cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Apatinib was the first anti-angiogenic agent approved for treatment of metastatic gastric cancer (GC). However, the emergence of resistance was inevitable. Thus investigating new and valuable off-target effect of apatinib directly against cancer cells is of great significance. Here, we identified extra spindle pole bodies-like 1 (ESPL1) was responsible for apatinib resistance in GC cells through CRISPR genome-wide gain-of-function screening. Loss of function studies further showed that ESPL1 inhibition suppressed cell proliferation, migration and promoted apoptosis in vitro, and accordingly ESPL1 knockdown sensitized GC cells to apatinib. In addition, we found ESPL1 interacted with mouse double minute 2 (MDM2), a E3 ubiquitin protein ligase, and the combination of MDM2 siRNA with apatinib synergistically ameliorated the resistance induced by ESPL1 overexpression. In summary, our study indicated that ESPL1 played a critical role in apatinib resistance in GC cells. Inhibition of MDM2 could rescue the sensitivity of GC cells to apatinib and reverse ESPL1-mediated resistance.
- Published
- 2024
- Full Text
- View/download PDF
37. MDM2 regulates the stability of AR, AR-V7, and TM4SF3 proteins in prostate cancer
- Author
-
Prabesh Khatiwada, Ujjwal Rimal, Zhengyang Han, and Lirim Shemshedini
- Subjects
ar ,ar-v7 ,tm4sf3 ,mdm2 ,prostate cancer ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Androgen receptor (AR) and its constitutively active splice variant, AR Variant 7 (AR-V7), regulate genes essential for the development and progression of prostate cancer. Degradation of AR and AR-V7 by the ubiquitination proteasomal pathway is important for the regulation of both their protein stability. Our published results demonstrate that the interaction of TM4SF3 with either AR or AR-V7 leads to mutual stabilization due to a reduction in their ubiquitination and proteasomal degradation. These results led us to search for a common E3 ligase for AR, AR-V7, and TM4SF3. Depletion by siRNA of several E3 ligases identified MDM2 as the common E3 ligase. MDM2 inhibition by siRNA depletion or using a pharmacological inhibitor (MDM2i) of its E3 ligase activity led to elevated levels of endogenous AR, AR-V7, and TM4SF3 in prostate cancer cells. MDM2 knockdown in PC-3 cells, which do not express AR, also increased TM4SF3, demonstrating that MDM2 affects the TM4SF3 protein independent of AR. We further demonstrate that MDM2i treatment reduced the ubiquitination of AR and TM4SF3, suggesting that MDM2 can induce the ubiquitination of these proteins. Increased AR and AR-V7 protein levels induced by MDM2i treatment resulted in the expected increased expression of AR-regulated genes and enhanced proliferation and migration of both LNCaP and Enzalutamide-resistant CWR-22Rv1 prostate cancer cells. Thus, our study expands the known roles of MDM2 in prostate cancer to include its potential involvement in the important mutual stabilization that TM4SF3 exhibits when interacting with either AR or AR-V7.
- Published
- 2024
- Full Text
- View/download PDF
38. The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway
- Author
-
Konstantinos Karakostis, Laurence Malbert-Colas, Aikaterini Thermou, Borek Vojtesek, and Robin Fåhraeus
- Subjects
MDM2 ,Synonymous mutations ,RNA secondary structure ,Genotoxic stress ,MRN complex ,DNA Damage Sensing ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The ATM kinase constitutes a master regulatory hub of DNA damage and activates the p53 response pathway by phosphorylating the MDM2 protein, which develops an affinity for the p53 mRNA secondary structure. Disruption of this interaction prevents the activation of the nascent p53. The link of the MDM2 protein—p53 mRNA interaction with the upstream DNA damage sensor ATM kinase and the role of the p53 mRNA in the DNA damage sensing mechanism, are still highly anticipated. Methods The proximity ligation assay (PLA) has been extensively used to reveal the sub-cellular localisation of the protein—mRNA and protein–protein interactions. ELISA and co-immunoprecipitation confirmed the interactions in vitro and in cells. Results This study provides a novel mechanism whereby the p53 mRNA interacts with the ATM kinase enzyme and shows that the L22L synonymous mutant, known to alter the secondary structure of the p53 mRNA, prevents the interaction. The relevant mechanistic roles in the DNA Damage Sensing pathway, which is linked to downstream DNA damage response, are explored. Following DNA damage (double-stranded DNA breaks activating ATM), activated MDMX protein competes the ATM—p53 mRNA interaction and prevents the association of the p53 mRNA with NBS1 (MRN complex). These data also reveal the binding domains and the phosphorylation events on ATM that regulate the interaction and the trafficking of the complex to the cytoplasm. Conclusion The presented model shows a novel interaction of ATM with the p53 mRNA and describes the link between DNA Damage Sensing with the downstream p53 activation pathways; supporting the rising functional implications of synonymous mutations altering secondary mRNA structures.
- Published
- 2024
- Full Text
- View/download PDF
39. Targeting MDM2 in malignancies is a promising strategy for overcoming resistance to anticancer immunotherapy
- Author
-
Dantong Sun, Haili Qian, Junling Li, and Puyuan Xing
- Subjects
Malignancies ,MDM2 ,Anticancer immunotherapy ,Tumor immune microenvironment ,Medicine - Abstract
Abstract MDM2 has been established as a biomarker indicating poor prognosis for individuals undergoing immune checkpoint inhibitor (ICI) treatment for different malignancies by various pancancer studies. Specifically, patients who have MDM2 amplification are vulnerable to the development of hyperprogressive disease (HPD) following anticancer immunotherapy, resulting in marked deleterious effects on survival rates. The mechanism of MDM2 involves its role as an oncogene during the development of malignancy, and MDM2 can promote both metastasis and tumor cell proliferation, which indirectly leads to disease progression. Moreover, MDM2 is vitally involved in modifying the tumor immune microenvironment (TIME) as well as in influencing immune cells, eventually facilitating immune evasion and tolerance. Encouragingly, various MDM2 inhibitors have exhibited efficacy in relieving the TIME suppression caused by MDM2. These results demonstrate the prospects for breakthroughs in combination therapy using MDM2 inhibitors and anticancer immunotherapy.
- Published
- 2024
- Full Text
- View/download PDF
40. TrkA promotes MDM2-mediated AGPS ubiquitination and degradation to trigger prostate cancer progression
- Author
-
Yu Zhang, Zhenlin Huang, Keqiang Li, Guoqing Xie, Yuankang Feng, Zihao Wang, Ningyang Li, Ruoyang Liu, Yinghui Ding, Jun Wang, Jinjian Yang, and Zhankui Jia
- Subjects
Prostate cancer ,Ferroptosis ,AGPS ,MDM2 ,TrkA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background As a novel necrosis manner, ferroptosis has been increasingly reported to play a role in tumor progression and treatment, however, the specific mechanisms underlying its development in prostate cancer remain unclear. Growing evidence showed that peroxisome plays a key role in ferroptosis. Herein, we identified a novel mechanism for the involvement of ferroptosis in prostate cancer progression, which may provide a new strategy for clinical treatment of prostate cancer. Methods Label-Free Mass spectrometry was used to screen and identify candidate proteins after ferroptosis inducer-ML210 treatment. Immunohistochemistry was undertaken to explore the protein expression of AGPS in prostate cancer tissues compared with normal tissues. Co-immunoprecipitation and GST pull-down were used to identify the directly binding of AGPS to MDM2 in vivo and in vitro. CCK8 assay and colony formation assay were used to illustrate the key role of AGPS in the progression of prostate cancer in vitro. The xenograft model was established to verify the key role of AGPS in the progression of prostate cancer in vivo. Results AGPS protein expression was downregulated in prostate cancer tissues compared with normal tissues from the first affiliated hospital of Zhengzhou University dataset. Lower expression was correlated with poorer overall survival of patients compared to those with high expression of AGPS. In addition, AGPS can promote ferroptosis by modulating the function of peroxisome-resulting in the lower survival of prostate cancer cells. Furthermore, it was shown that AGPS can be ubiquitinated and degraded by the E3 ligase-MDM2 through the proteasomal pathway. Meanwhile, kinase TrkA can promote the combination of AGPS and MDM2 by phosphorylating AGPS at Y451 site. It was verified that kinase TrkA inhibitor—Larotrectinib can increase the susceptibility of prostate cancer cells to ferroptosis, which leads to the inhibition of prostate cancer proliferation to a great extent in vitro and in vivo. Conclusion Based on these findings, we proposed the combination of ferroptosis inducer and TrkA inhibitor to synergistically exert anti-tumor effects, which may provide a new strategy for the clinical treatment of prostate cancer.
- Published
- 2024
- Full Text
- View/download PDF
41. USP7 reduces the level of nuclear DICER, impairing DNA damage response and promoting cancer progression
- Author
-
Xiaojia Liu, Runhui Lu, Qianqian Yang, Jianfeng He, Caihu Huang, Yingting Cao, Zihan Zhou, Jiayi Huang, Lian Li, Ran Chen, Yanli Wang, Jian Huang, Ruiyu Xie, Xian Zhao, and Jianxiu Yu
- Subjects
cancer progression ,DICER ,MDM2 ,ubiquitination ,USP7 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Endoribonuclease DICER is an RNase III enzyme that mainly processes microRNAs in the cytoplasm but also participates in nuclear functions such as chromatin remodelling, epigenetic modification and DNA damage repair. The expression of nuclear DICER is low in most human cancers, suggesting a tight regulation mechanism that is not well understood. Here, we found that ubiquitin carboxyl‐terminal hydrolase 7 (USP7), a deubiquitinase, bounded to DICER and reduced its nuclear protein level by promoting its ubiquitination and degradation through MDM2, a newly identified E3 ubiquitin‐protein ligase for DICER. This USP7‐MDM2‐DICER axis impaired histone γ‐H2AX signalling and the recruitment of DNA damage response (DDR) factors, possibly by influencing the processing of small DDR noncoding RNAs. We also showed that this negative regulation of DICER by USP7 via MDM2 was relevant to human tumours using cellular and clinical data. Our findings revealed a new way to understand the role of DICER in malignant tumour development and may offer new insights into the diagnosis, treatment and prognosis of cancers.
- Published
- 2024
- Full Text
- View/download PDF
42. MDM2 inhibitors in cancer immunotherapy: Current status and perspective
- Author
-
Qinru Zeng, Shaocheng Zeng, Xiaofeng Dai, Yun Ding, Chunye Huang, Ruiwen Ruan, Jianping Xiong, Xiaomei Tang, and Jun Deng
- Subjects
Immune hyperprogression ,Immune microenvironment ,Immunotherapy ,MDM2 ,MDM2 inhibitors ,p53 ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Murine double minute 2 (MDM2) plays an essential role in the cell cycle, apoptosis, DNA repair, and oncogene activation through p53-dependent and p53-independent signaling pathways. Several preclinical studies have shown that MDM2 is involved in tumor immune evasion. Therefore, MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention. In recent years, immune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic. However, the effectiveness of a single agent is only approximately 20%–40%, which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins. Here, we reviewed the role of MDM2 in regulating the immune microenvironment, tumor immune evasion, and hyperprogression during immunotherapy. In addition, we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tumors with MDM2 overexpression or amplification. The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.
- Published
- 2024
- Full Text
- View/download PDF
43. Case report: An atypical case of uterine adenosarcoma with extensive bizarre stromal cells and amplification of MDM2.
- Author
-
Xiaoling Xiao and Ying He
- Subjects
STROMAL cells ,FLUORESCENCE in situ hybridization ,BENIGN tumors ,EPITHELIAL tumors ,CARCINOSARCOMAS ,DNA sequencing ,ENDOMETRIAL tumors - Abstract
Polypoid lesions in the uterus are very common. There are a lot of benign lesions and malignant tumor should be considered. Adenosarcoma, one of the differential diagnoses, is a rare mixed epithelial and mesenchymal tumor consisting of benign epithelial components and sarcoma stroma. Here, we present a case of atypical adenosarcoma that has never been reported. This tumor was composed of benign endometrial epithelium and hyperplastic stroma with extensive bizarre stromal cells. But the cleft-like spaces and papillary stomal fronds which were the typical histological images of adenosarcoma were absent. These stomal cells, including bizarre cells, were positive for vimentin, CD10, ER, PR, cyclin D1 and P16 but were immunonegative for caldesmon. Furthermore, this tumor harbored amplification of MDM2, as revealed by fluorescence in situ hybridization testing (FISH) and next-generation DNA sequencing (NGS). [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
44. p53 biology and reactivation for improved therapy in MDS and AML.
- Author
-
Zawacka, Joanna E.
- Subjects
ACUTE myeloid leukemia ,P53 protein ,MYELODYSPLASTIC syndromes ,BIOLOGY ,CYTOPENIA ,PROTEOLYSIS - Abstract
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) originate from preleukemic hematopoietic conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS) and have variable outcomes despite the successful implementation of targeted therapies. The prognosis differs depending on the molecular subgroup. In patients with TP53 mutations, the most inferior outcomes across independent studies were observed. Myeloid malignancies with TP53 mutations have complex cytogenetics and extensive structural variants. These factors contribute to worse responses to induction therapy, demethylating agents, or venetoclax-based treatments. Survival of patients with biallelic TP53 gene mutations is often less than one year but this depends on the type of treatment applied. It is still controversial whether the allelic state of mutant TP53 impacts the outcomes in patients with AML and high-risk MDS. Further studies are needed to justify estimating TP53 LOH status for better risk assessment. Yet, TP53-mutated MDS, MDS/AML and AML are now classified separately in the International Consensus Classification (ICC). In the clinical setting, the wild-type p53 protein is reactivated pharmacologically by targeting p53/MDM2/MDM4 interactions and mutant p53 reactivation is achieved by refolding the DNA binding domain to wild-type-like conformation or via targeted degradation of the mutated protein. This review discusses our current understanding of p53 biology in MDS and AML and the promises and failures of wild-type and mutant p53 reactivation in the clinical trial setting. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
45. Hyperfunction of post-synaptic density protein 95 promotes seizure response in early-stage aβ pathology.
- Author
-
Yook, Yeeun, Lee, Kwan Young, Kim, Eunyoung, Lizarazo, Simon, Yu, Xinzhu, and Tsai, Nien-Pei
- Abstract
Accumulation of amyloid-beta (Aβ) can lead to the formation of aggregates that contribute to neurodegeneration in Alzheimer's disease (AD). Despite globally reduced neural activity during AD onset, recent studies have suggested that Aβ induces hyperexcitability and seizure-like activity during the early stages of the disease that ultimately exacerbate cognitive decline. However, the underlying mechanism is unknown. Here, we reveal an Aβ-induced elevation of postsynaptic density protein 95 (PSD-95) in cultured neurons in vitro and in an in vivo AD model using APP/PS1 mice at 8 weeks of age. Elevation of PSD-95 occurs as a result of reduced ubiquitination caused by Akt-dependent phosphorylation of E3 ubiquitin ligase murine-double-minute 2 (Mdm2). The elevation of PSD-95 is consistent with the facilitation of excitatory synapses and the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induced by Aβ. Inhibition of PSD-95 corrects these Aβ-induced synaptic defects and reduces seizure activity in APP/PS1 mice. Our results demonstrate a mechanism underlying elevated seizure activity during early-stage Aβ pathology and suggest that PSD-95 could be an early biomarker and novel therapeutic target for AD. Synopsis: Neuronal hyperactivity and elevated susceptibility to seizures have been observed in early stage of Alzheimer's disease. Accumulation of Aβ leads to an elevation of excitatory synapse numbers and seizure susceptibility, which can be ameliorated by inhibition of PSD-95. Post-synaptic density protein 95 (PSD-95) is elevated in young APP/PS1 mice as well as cultured cortical neurons treated with synthetic Aβ peptides. Elevated PSD-95 is caused by its reduced ubiquitination resulting from Akt-dependent phosphorylation of E3 ubiquitin ligase Mdm2. Genetically inhibiting PSD-95 reduces Aβ-induced elevation of excitatory synapse numbers. Genetically inhibiting PSD-95 ameliorates seizure response in APP/PS1 mice as well as wildtype mice injected with synthetic Aβ peptides. Neuronal hyperactivity and elevated susceptibility to seizures have been observed in early stage of Alzheimer's disease. Accumulation of Aβ leads to an elevation of excitatory synapse numbers and seizure susceptibility, which can be ameliorated by inhibition of PSD-95. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
46. Jun Dimerization Protein 2 (JDP2) Increases p53 Transactivation by Decreasing MDM2.
- Author
-
Price, Kasey, Yang, William H., Cardoso, Leticia, Wang, Chiung-Min, Yang, Richard H., and Yang, Wei-Hsiung
- Subjects
- *
T-test (Statistics) , *RESEARCH funding , *PLASMIDS , *TRANSCRIPTION factors , *TUMOR markers , *MANN Whitney U Test , *TUMOR suppressor genes , *CELL lines , *CELL culture , *WESTERN immunoblotting , *METABOLISM - Abstract
Simple Summary: Cancer is the leading cause of death in the United States and worldwide. The current study demonstrates how JDP2, part of AP-1 protein complex, interacts with p53 tumor suppressor. The results show that JDP2 binds to p53, increases p53 transactivation, and helps stabilize p53. JDP2 also binds MDM2, the major negative regulator of p53. This suggests that JDP2 is a new regulator of p53-MDM2 pathway. The AP-1 protein complex primarily consists of several proteins from the c-Fos, c-Jun, activating transcription factor (ATF), and Jun dimerization protein (JDP) families. JDP2 has been shown to interact with the cAMP response element (CRE) site present in many cis-elements of downstream target genes. JDP2 has also demonstrates important roles in cell-cycle regulation, cancer development and progression, inhibition of adipocyte differentiation, and the regulation of antibacterial immunity and bone homeostasis. JDP2 and ATF3 exhibit significant similarity in their C-terminal domains, sharing 60–65% identities. Previous studies have demonstrated that ATF3 is able to influence both the transcriptional activity and p53 stability via a p53-ATF3 interaction. While some studies have shown that JDP2 suppresses p53 transcriptional activity and in turn, p53 represses JDP2 promoter activity, the direct interaction between JDP2 and p53 and the regulatory role of JDP2 in p53 transactivation have not been explored. In the current study, we provide evidence, for the first time, that JDP2 interacts with p53 and regulates p53 transactivation. First, we demonstrated that JDP2 binds to p53 and the C-terminal domain of JDP2 is crucial for the interaction. Second, in p53-null H1299 cells, JDP2 shows a robust increase of p53 transactivation in the presence of p53 using p53 (14X)RE-Luc. Furthermore, JDP2 and ATF3 together additively enhance p53 transactivation in the presence of p53. While JDP2 can increase p53 transactivation in the presence of WT p53, JDP2 fails to enhance transactivation of hotspot mutant p53. Moreover, in CHX chase experiments, we showed that JDP2 slightly enhances p53 stability. Finally, our findings indicate that JDP2 has the ability to reverse MDM2-induced p53 repression, likely due to decreased levels of MDM2 by JDP2. In summary, our results provide evidence that JDP2 directly interacts with p53 and decreases MDM2 levels to enhance p53 transactivation, suggesting that JDP2 is a novel regulator of p53 and MDM2. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
47. Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain.
- Author
-
Huang, Yanping, Flentke, George R., Rivera, Olivia C., Saini, Nipun, Mooney, Sandra M., and Smith, Susan M.
- Subjects
- *
NEURAL stem cells , *FETAL brain , *ORGANELLE formation , *PRENATAL alcohol exposure , *RIBOSOMAL proteins , *CELL cycle , *APOPTOSIS - Abstract
Prenatal alcohol exposure (PAE) is a leading cause of neurodevelopmental disability through its induction of neuronal growth dysfunction through incompletely understood mechanisms. Ribosome biogenesis regulates cell cycle progression through p53 and the nucleolar cell stress response. Whether those processes are targeted by alcohol is unknown. Pregnant C57BL/6J mice received 3 g alcohol/kg daily at E8.5–E17.5. Transcriptome sequencing was performed on the E17.5 fetal cortex. Additionally, primary neural stem cells (NSCs) were isolated from the E14.5 cerebral cortex and exposed to alcohol to evaluate nucleolar stress and p53/MDM2 signaling. Alcohol suppressed KEGG pathways involving ribosome biogenesis (rRNA synthesis/processing and ribosomal proteins) and genes that are mechanistic in ribosomopathies (Polr1d, Rpl11; Rpl35; Nhp2); this was accompanied by nucleolar dissolution and p53 stabilization. In primary NSCs, alcohol reduced rRNA synthesis, caused nucleolar loss, suppressed proliferation, stabilized nuclear p53, and caused apoptosis that was prevented by dominant-negative p53 and MDM2 overexpression. Alcohol's actions were dose-dependent and rapid, and rRNA synthesis was suppressed between 30 and 60 min following alcohol exposure. The alcohol-mediated deficits in ribosomal protein expression were correlated with fetal brain weight reductions. This is the first report describing that pharmacologically relevant alcohol levels suppress ribosome biogenesis, induce nucleolar stress in neuronal populations, and involve the ribosomal/MDM2/p53 pathway to cause growth arrest and apoptosis. This represents a novel mechanism of alcohol-mediated neuronal damage. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
48. Efficacy and Safety of the MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced Biliary Tract Cancer: A Case Series.
- Author
-
Yamamoto, Noboru, Tolcher, Anthony, Hafez, Navid, Lugowska, Iwona, Ramlau, Rodryg, Macarulla, Teresa, Geng, Junxian, Li, Jian, Teufel, Michael, Märten, Angela, and LoRusso, Patricia
- Subjects
- *
GALLBLADDER cancer , *TERMINATION of treatment , *BILIARY tract , *ADVERSE health care events , *COMBINATION drug therapy ,BILIARY tract cancer - Abstract
Background: In patients with advanced biliary tract cancer (BTC), first-line chemotherapy plus immunotherapy has improved outcomes; however, second-line options that reflect the disease's molecular heterogeneity are still needed. One emerging target is MDM2, amplified in ~5– 8% of BTC cases. Methods: This is a subset analysis of two ongoing Phase Ia/Ib trials assessing patients treated with brigimadlin (BI 907828; a highly potent, oral MDM2–p53 antagonist) ± ezabenlimab (PD-1 inhibitor) ± BI 754111 (anti-LAG-3; n = 1). Results: Results from 12 patients with BTC are shown (monotherapy: n = 6/combination: n = 6). Six patients achieved partial response (monotherapy: n = 2/combination: n = 4), four had stable disease; responses were durable. Brigimadlin had a manageable safety profile. Seven patients had dose reductions due to adverse events, but no treatment-related adverse events led to treatment discontinuation. Conclusion: Brigimadlin demonstrated anti-tumor activity in patients with advanced MDM2-amplified BTC, and warrants further investigation. Plain Language Summary: Biliary tract carcinoma (BTC) is a cancer that affects the bile ducts which are part of the digestive system. Usually, the first treatment for advanced BTC (ie cannot be removed surgically and/or has spread) is chemotherapy in combination with immunotherapy. However, if chemotherapy does not work, or stops working, there are few treatment options available in second-line. Accordingly, intensive research is ongoing to try and find effective drugs. One potential medicine, called brigimadlin (or BI 907828), is a tablet that activates a molecule in tumor cells called p53. The normal function of p53 is to kill cells when they first start to become cancerous. However, if p53 is turned off by genetic mutations, or other mechanisms, then cancer can develop. Although p53 is rarely mutated in BTC tumors, it is inactivated by another molecule called MDM2 which is usually present at abnormally high levels in BTC. Brigimadlin prevents interaction between MDM2 and p53. This activates p53 and causes the cancer to die. Two clinical trials are currently assessing brigimadlin in a range of cancers, including BTC, with the aim of identifying a safe dose that can be examined in more detail in larger trials. So far, 12 patients with BTC have been treated. The patients' tumors significantly shrank in six of these patients and remained stable in a further four patients. Side effects were as expected and could be tolerated by pausing treatment or lowering the dose. These results show that brigimadlin should be tested further in patients with advanced BTC. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
49. Comparative Expression Analysis of TP53 Tumor Suppressor and MDM2 Oncogene in Colorectal Adenocarcinoma.
- Author
-
NIOTIS, ATHANASIOS, DIMITROULIS, DIMITRIOS, SPYROPOULOU, DESPOINA, TSIAMBAS, EVANGELOS, SARLANIS, HELEN, DAVRIS, DIMITRIOS, FALIDAS, EVANGELOS, KAVANTZAS, NIKOLAOS, PESCHOS, DIMITRIOS, MANAIOS, LOUKAS, and KONSTANTINIDIS, KONSTANTINOS C.
- Subjects
TUMOR suppressor proteins ,GENE expression ,ONCOGENES ,PROTEIN overexpression ,P53 protein ,HEREDITARY nonpolyposis colorectal cancer - Abstract
Background/Aim: The tumor protein 53 (TP53) tumor suppressor protein (17p13.1) acts as a significant regulator for the cell cycle normal function. The gene is frequently mutated in colorectal adenocarcinoma (CRC) patients and is associated to poor prognosis and low response rates to chemo-targeted therapy. Our purpose was to correlate TP53 expression with Mouse Double Minute 2 Homolog (MDM2), a proto-oncogene (12q14.3) and a major negative regulator in the TP53-MDM2 auto-regulatory pathway. Materials and Methods: A total of forty (n=40) colorectal adenocarcinoma (CRC) cases were included in this study. An immunohistochemistry-based assay was implemented by using anti-TP53 and anti-MDM2 antibodies in the corresponding tissue sections. Additionally, a digital image analysis assay was implemented for objectively measuring TP53/MDM2 immunostaining intensity levels. Results: TP53 protein overexpression was detected in 27/40 (67.5%), whereas MDM2 overexpression in 28/40 (70%) cases. Interestingly, in 21/40 (52.5%) cases, a combined TP53/MDM2 co-expression was detected, whereas in 6/40 (15%), a combined loss of expression was identified (overall co-expression: p=0.119). p53 overexpression was significantly correlated to grade of the examined cases (p=0.001), whereas MDM2 to stage and max diameter of the malignancies (p=0.001 and 0.024, respectively). Conclusion: TP53/MDM2 over expression is a frequent and significant genetic event in CRCs associated with an aggressive biological behavior, as a result of increased dedifferentiation grade and advanced stage/elevated tumor volume, respectively. MDM2 oncogene overactivation combined with mutated and overexpressed TP53 is observed in sub-groups of patients leading to specific gene/protein signatures - targets for personalized chemotherapeutic approaches. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
50. Genome-wide CRISPR screen identifies ESPL1 limits the response of gastric cancer cells to apatinib.
- Author
-
Zhang, Bei, Chen, Yan, Chen, Xinqi, Ren, Zhiyao, Xiang, Hong, Mao, Lipeng, and Zhu, Guodong
- Subjects
- *
APATINIB , *STOMACH cancer , *CANCER cells , *CRISPRS , *MEDICAL screening - Abstract
Apatinib was the first anti-angiogenic agent approved for treatment of metastatic gastric cancer (GC). However, the emergence of resistance was inevitable. Thus investigating new and valuable off-target effect of apatinib directly against cancer cells is of great significance. Here, we identified extra spindle pole bodies-like 1 (ESPL1) was responsible for apatinib resistance in GC cells through CRISPR genome-wide gain-of-function screening. Loss of function studies further showed that ESPL1 inhibition suppressed cell proliferation, migration and promoted apoptosis in vitro, and accordingly ESPL1 knockdown sensitized GC cells to apatinib. In addition, we found ESPL1 interacted with mouse double minute 2 (MDM2), a E3 ubiquitin protein ligase, and the combination of MDM2 siRNA with apatinib synergistically ameliorated the resistance induced by ESPL1 overexpression. In summary, our study indicated that ESPL1 played a critical role in apatinib resistance in GC cells. Inhibition of MDM2 could rescue the sensitivity of GC cells to apatinib and reverse ESPL1-mediated resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.