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Background: The aim of this study was to construct a prognostic model of colon cancer based on demethylation-related genes. An in-depth understanding of the relationship between the set of demethylated genes and colon cancer not only assists in revealing the pathogenesis of colon cancer but also provides strong support for future therapeutic strategies and individualized medicine., Methods: Data were obtained from the TCGA database and the GEO-GSE39582 cohort. A risk score model for demethylation-related genes was developed using univariate Cox regression analysis and LASSO regression analysis. The accuracy and reliability of the model were confirmed using K-M survival analysis and ROC curve analysis. Additionally, a nomogram was created by integrating the risk score and clinicopathological variables. Finally, the biological function of the RCOR2 gene was verified by performing qPCR, MTT, colony formation, Transwell, and subcutaneous tumor formation assays in nude mice., Results: We constructed a risk score model containing 30 demethylation-related genes for predicting the survival risk of patients with colon cancer. COAD patients were categorized into high-risk and low-risk groups, and Kaplan-Meier (KM) curve analysis revealed that the high-risk group was associated with a worse prognosis. Univariate and multivariate Cox regression analyses validated the risk score as an independent prognostic factor for COAD. We also analyzed the differences in the sensitivity to nine chemotherapeutic agents and small molecule targeted drugs between the high-risk and low-risk groups. Moreover, we performed experiments in COAD cell lines and nude mice to verify that RCOR2 was differentially expressed between tumor tissues and normal tissues and that high RCOR2 expression promoted a malignant phenotype of colon cancer., Conclusion: This study demonstrated the potential roles of demethylation-related genes in colon cancer by conducting a comprehensive analysis and constructing a risk score. These findings also highlight the ability of these genes to indicate patient prognosis and tumor immune microenvironment. Furthermore, this study provides a reliable predictive tool that can assist in guiding the treatment and management of colon cancer patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Liver cancer is the fourth leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. APG-1252 is a small molecule inhibitor targeting Bcl-2 and Bcl-xl. However, its anti-tumor effects in HCC, alone or in combination with Cabozantinib, have not been extensively studied., Experimental: Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western blot was employed to detect the protein expression levels. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by transwell assay. Huh7 xenograft model in nude mice was used to investigate the combination antitumor effect in vivo., Key Results: Our study demonstrated that APG-1252 monotherapy inhibited the proliferation and migration ability of HCC cells, and induced HCC cells apoptosis. The combination of APG-1252 and Cabozantinib showed significant synergistic antitumor effects. Furthermore, the in vivo experiment demonstrated that the combination therapy exerted a synergistic effect in delaying tumor growth, notably downregulating MEK/ERK phosphorylation levels. In terms of mechanism, Cabozantinib treatment caused an increase in the phosphorylation levels of CREB and Bcl-xl proteins, while the combination with APG-1252 mitigated this effect, thereby enhanced the antitumor effect of Cabozantinib., Conclusion and Implications: Our findings suggest that APG-1252 in combination with Cabozantinib offers a more effective treatment strategy for HCC patients, warranting further clinical investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A multi-component paclitaxel (PTX) -loaded β-elemene nanoemulsion by transferrin modification (Tf-PE-MEs) was developed to enhance non-small-cell lung cancer (NSCLC) treatment. After transferrin modification, the particle size of Tf-PE-MEs was (14.87 ± 1.84) nm, and the zeta potential was (-10.19 ± 0.870) mV, respectively. In vitro experiments showed that Tf-PE-MEs induced massive apoptosis in A549 cells, indicating that it had significant cytotoxicity to A549 cells. Through transferrin modification, Tf-PE-MEs accumulated at the tumor site efficiently with overexpressed transferrin receptor (TfR) on the surface of A549 cells. This will allow increasing PTX and β-elemene concentration in the target cells, enhancing the therapeutic effect. Compared to PTX alone, Tf-PE-MEs displayed good anti-tumor efficacy and diminished systemic toxicity in vivo studies. With favourable therapeutic potential, this study provides a new strategy for the combined anticancer treatment of non-small cell lung cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: In developed countries, endometrial cancer (EC) is the most prevalent gynecological cancer and its occurrence is associated with chronic inflammation. ATP5F1D is a subunit of ATP synthase (complex V), as well as the important component of mitochondrial electron transport chain (ETC). ETC play compelling roles in carcinogenesis. To date, little is known about the role of ATP5F1D in EC., Methods: ATP5F1D expression was identified in EC tissues and EC cell lines. We evaluated the influence of ATP5F1D on clinical features and prognosis based on TCGA database. The effects of ATP5F1D in EC malignant progression by applying loss-of-function assays in KLE and Ishikawa cell lines were detected by EdU, CCK-8, wound healing, Transwell, and flow cytometry assays. Additionally, electron microscope, LDH release, ELISA, mitochondrial ROS measurement, and Immunofluorescence were performed to demonstrate ATP5F1D can affect the pyroptosis of EC. To observe the anti-tumor effect on ATP5F1D silencing, we established an in vivo human endometrial tumor model using nude mice., Results: ATP5F1D expression was significantly upregulated in EC and was associated with favorable prognosis. ATP5F1D knockdown inhibited the proliferation, invasion, and migration of EC cells. Similarly, in nude mice, ATP5F1D knockdown suppressed the growth EC cells. Knocking down ATP5F1D lead to decrease the production of mitochondrial ROS (mtROS) and inhibited pyroptosis of EC cells., Conclusion: Downregulation of ATP5F1D as a new therapeutic strategy that could mediate pyroptosis via suppressing mtROS/NLRP3/caspase-1/GSDMD pathway to inhibit EC progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: A newly identified type of cell death due to intracellular copper accumulation is known as cuproptosis and RNA methylation is a post-transcriptional modification mechanism, both of which perform vital roles in the immune microenvironment of colorectal cancer (CRC), but the link between the two needs more research., Methods: TCGA database provided RNA-seq data and details clinically of CRC samples. Cuproptosis-related RNA methylation regulators (CRRMRs) were identified by correlation analysis. We screened 6 CRRMRs for prognostic model construction by employing LASSO-Cox regression analysis and calculated risk scores by CRRMRs (CuMS). GSE39582 and GSE38832 cohort were used as external validation sets. This research concentrated on the connection between the prognostic model and somatic mutation, anti-cancer drug sensitivity, immune infiltration, immune checkpoint expression. In addition, we investigated the differential expression of YTHDC2 in epithelial cell subpopulations by single-cell analysis with GSE166555, calculated cuproptosis scores and performed pathway enrichment. In vitro experiments were performed to explore the consequences of knockdown of YTHDC2 on CRC cell proliferation and migration, as well as changes in CRC cell viability in response to elesclomol after knockdown of YTHDC2. In vivo experiments, we constructed the cell line-derived xenograft model to further validate the results of the in vitro experiments., Results: The prognosis of CRC can be predicted by CuMS, which GSE39582 and GSE38832 confirmed. Two CuMS groups showed different tumor mutation burden (TMB) and immune infiltration. CuMS was connected to emerging immune checkpoints CD47 and PVR, therefore, it can be clinically complementary to TMB and microsatellite instability (MSI) status. In single-cell analysis, a subpopulation of epithelial cells with high YTHDC2 expression had a high cuproptosis score. In vitro experiments, knocking down YTHDC2 promoted cell proliferation and migration in CRC, and weaken the inhibitory effect of elesclomol and elesclomol-Cu on cell viability, which in vivo experiments validated., Conclusion: We developed a prognostic model constructed by 6 CRRMRs to assess overall survival and immune microenvironment of CRC patients. YTHDC2 might regulate cuproptosis in multiple ways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The resistance of osteosarcoma (OS) to ionizing radiation (IR) is an obstacle for effective patient treatment. Apurinic/apyrimidinic endonuclease-reduction/oxidation factor 1 (APE1/Ref-1) is a multifunctional protein with DNA repair and reduction/oxidation (redox) activities. We previously revealed the role of APE1 in OS radioresistance; however, whether the redox activity of APE1 is involved in OS radioresistance is unclear. APE1 regulates the activation of ataxia-telangiectasia mutated (ATM), an initiator of DNA damage response that mediates radioresistance in other cancers. The role of APE1 redox activity and ATM activation in OS radioresistance is unknown. Our study revealed that IR increased APE1 expression and ATM activation in OS cells, and APE1 directly regulated ATM activation by its redox activity. The combined use of an APE1 redox inhibitor and ATM inhibitor effectively sensitized OS cells to IR in vitro and in vivo. Mechanistically, the increased radiosensitization of OS cells by the combined use of the two inhibitors was mediated by increased ferroptosis. Co-treatment with the two inhibitors significantly decreased expression of the common targeted transcription factor P53 compared with single inhibitor treatment. Collectively, APE1 redox activity, ATM activation and their crosstalk play important roles in the resistance of OS to irradiation. Synergetic inhibition of APE1 redox activity and ATM activation sensitized OS cells to IR by inducing ferroptosis, which provides a promising strategy for OS radiotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lipid droplet (LD) accumulation is one of the features in various tumors, whereas the significance of LD accumulation in pancreatic cancer progression remains unclear under chemotherapeutic condition. Since chemoresistance towards gemcitabine (GEM) is an obstacle for clinical therapy of pancreatic cancer, we sought to investigate the contribution of LD accumulation to GEM resistance. Herein, triacsin C (an inhibitor of LD production) dampened the proliferation, migration, and invasion of pancreatic cancer cells. The inhibition of LD accumulation induced by triacsin C or silencing of perilipin 2 (a marker of LD) sensitized cells to GEM treatment. Next, 75 paraffin-embedded samples and 5 pairs of frozen samples from pancreatic cancer patients were obtained for the detection of lysophosphatidylcholine acyltransferase 2 (LPCAT2; a LD-located enzyme contributing phosphatidylcholine synthesis) expression. The results revealed that LPCAT2 was upregulated in pancreatic cancer tissues, and its expression was correlated with clinical parameters and the basal LD content of cancer cell lines. Loss of LPCAT2 repressed the LD accumulation, GEM resistance, and cell motility. The enhancement of chemotherapy sensitivity was further confirmed in a xenograft model of mice in vivo. The carcinogenesis role of LPCAT2 was at least partly mediated by the LD accumulation. Then, signal transducer and activator of transcription 5B (STAT5B) activated the transcription of LPCAT2. Both LPCAT2 downregulation and triacsin C reversed the STAT5B-induced potentiation of malignant phenotypes in pancreatic cancer cells. In conclusion, LPCAT2-mediated lipid droplet production supported pancreatic cancer chemoresistance and cell motility, which was triggered by STAT5B., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The transforming growth factor-β (TGF-β) signaling pathway is pivotal in inducing epithelial-mesenchymal transition (EMT) and promoting cancer metastasis. Long non-coding RNAs (lncRNAs) have emerged as significant players in these processes, yet their precise mechanisms remain elusive. Here, we demonstrate that TGF-β-upregulated lncRNA 1 (TBUR1) is significantly activated by TGF-β via Smad3/4 signaling in lung adenocarcinoma (LUAD) cells. Functionally, TBUR1 triggers EMT, enhances LUAD cell migration and invasion in vitro, and promotes metastasis in nude mice. Mechanistically, TBUR1 interacts with heterogeneous nuclear ribonucleoprotein C (hnRNPC) to stabilize GRB2 mRNA in an m 6 A-dependent manner. Clinically, TBUR1 is upregulated in LUAD tissues and correlates with poor prognosis, highlighting its potential as a prognostic biomarker and therapeutic target for LUAD. Taken together, our findings underscore the crucial role of TBUR1 in mediating TGF-β-induced EMT and metastasis in LUAD, providing insights for future therapeutic interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Pancreatic cancer is a highly aggressive and lethal carcinoma. Circular RNAs (circRNAs) serve key regulatory functions in pancreatic cancer. Ferroptosis was induced by erastin treatment and analyzed by examining malondialdehyde (MDA), iron, Fe 2+ and glutathione (GSH). C11-BODIPY 581/591 was used to stain cells for analyzing lipid peroxidation. RNA immunoprecipitation, pull-down and chromatin immunoprecipitation assays were applied to evaluate intermolecular interaction. Mice received subcutaneous injection of pancreatic cancer cells as a model of subcutaneous tumor for in vivo tests. Circ_0005397 was abundantly expressed in pancreatic cancer, and its upregulation was associated with low survival of patients with pancreatic cancer. Circ_0005397 expression was induced by EIF4A3. PCBP2 was highly expressed in pancreatic cancer, and circ_0005397 and PCBP2 were positively correlated in patients with pancreatic cancer. Circ_0005397 knockdown sensitized pancreatic carcinoma cells to ferroptosis via downregulating PCBP2. Circ_0005397 promoted PCBP2 transcription via facilitating the binding of KAT6A and H3K9ac to PCBP2 promoter. Silencing of circ_0005397 reduced tumor growth by enhancing erastin-induced ferroptosis in vivo. EIF4A3-induced circ_0005397 inhibited erastin-induced ferroptosis in pancreatic cancer by promoting PCBP2 expression through KAT6A and H3K9ac., (© 2024 Federation of American Societies for Experimental Biology.)

Most patients diagnosed with pancreatic cancer are initially at an advanced stage, and radiotherapy resistance impact the effectiveness of treatment. This study aims to investigate the effects of endocrine disruptor Di-(2-ethylhexyl) phthalate (DEHP) on various biological behaviors and the radiotherapy sensitivity of pancreatic cancer cells, as well as its potential mechanisms. Our findings indicate that exposure to DEHP promotes the proliferation of various cancer cells, including those from the lung, breast, pancreas, and liver, in a time- and concentration-dependent manner. Furthermore, DEHP exposure could influence several biological behaviors of pancreatic cancer cells in vivo and vitro. These effects include reducing cell apoptosis, causing G0/G1 phase arrest, increasing migration capacity, enhancing tumorigenicity, elevating the proportion of cancer stem cells (CSCs), and upregulating expression levels of CSCs markers such as CD133 and BMI1. DEHP exposure can also increase radiation resistance, which can be reversed by downregulating BMI1 expression. In summary our research suggests that DEHP exposure can lead to pancreatic cancer progression and radiotherapy resistance, and the mechanism may be related to the upregulation of BMI1 expression, which leads to the increase of CSCs properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

While tyrosine kinase inhibitor resistance in cancer is a critical issue in the medical field, it is important for clinical testing as well, since it affects the ultimate outcome of cancer therapy. Yet, no effective solutions have been implemented till date. Clinical observations after tyrosine kinase inhibitor treatment reveal that acquired resistance inevitably limits the curative effects of non-small cell lung cancer treatment because of mutations in the epidermal growth factor receptor gene, which are accompanied by epithelial-mesenchymal transition. Here, for the first time, we report that the transmembrane glycoprotein CD44, which is associated with epithelial-mesenchymal transition, chemoresistance, and cancer progression, mediates enhanced endocytosis of iron-platinum alloy nanoparticles (FePt NPs) in the mesenchymal-state gefitinib-resistant (GR+ and M6) cells, via the binding of the CD44 ligand, hyaluronan, to the surface-absorbed hyaluronan-binding protein 2. Upon treatment with FePt NPs, there was higher cellular uptake in mesenchymal-state GR+ and M6 cells, resulting from cell death through ferroptosis and mitochondrial dysfunction, as compared to that observed in the epithelial-state cells. Mechanistically, inactivation of dihydroorotate dehydrogenase elevated the production of mitochondrial lipid peroxidation, and enhanced the cell death in the epithelial-state HCC827 cells, thereby indicating its role in defense against FePt NPs-induced ferroptosis. Furthermore, induction of ferroptosis has been shown to specifically promote the cell death of drug-tolerant "persister" cells and reverse their resistance as well. Therefore, we concluded that FePt NPs preferentially target mesenchymal drug-tolerant "persister" cells and promote ferroptosis, to overcome their resistance. STATEMENT OF SIGNIFICANCE: In the present study, we identified FePt NPs as an innovative agent for cancer treatment, particularly in mesenchymal-state cells that exhibit TKI resistance. Mesenchymal-state cancer cells showed enhanced uptake of FePt NPs via CD44-HA-mediated endocytosis, accompanied by severe cell death and mitochondrial morphology alterations, in comparison to epithelial-state cells. We further elucidated the mechanism underlying FePt NPs-induced ferroptotic cell death as via a burst of mitochondrial LPO and DHODH protein inactivation. In addition, we found that FePt NPs inhibit tumor growth in TKI-resistant mesenchymal GR+ cell-bearing mice with better efficacy than the ferroptotic inducer RSL3. Our current findings on using FePt NPs to overcome TKI resistance through ferroptosis activation may offer a alternative strategy for improved cancer treatment., Competing Interests: Declaration of Competing Interests The authors declare no potential conflicts of interest., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Mini-chromosome maintenance protein 2 (MCM2) is a potential target for the development of cancer therapeutics. However, small molecule inhibitors targeting MCM2 need further investigation., Methods: Molecular dynamics simulation was performed to identify active pockets in the MCM2 protein structure (6EYC). The active pocket was used as a docking model to discover MCM2 inhibitors by using structure-based virtual screening and surface plasmon resonance (SPR) assay. Furthermore, the efficacy of pixantrone targeting MCM2 in ovarian cancer was evaluated in vitro and in vivo., Results: Pixantrone was identified as a novel inhibitor of MCM2 by virtual screening. SPR binding affinity analysis confirmed the direct binding of pixantrone to MCM2 protein. Pixantrone significantly reduced the viability of ovarian cancer cells A2780 and SKOV3 in a dose- and time-dependent manner. In addition, pixantrone inhibited DNA replication, and induced cell cycle arrest and apoptosis in ovarian cancer cells via targeting MCM2. Knockdown of MCM2 could attenuate the inhibitory activity of pixantrone in ovarian cancer cells. Furthermore, pixantrone significantly suppressed ovarian cancer growth in the A2780 cell xenograft mouse model and showed favorable safety., Conclusion: These findings suggest that pixantrone may be a promising drug for ovarian cancer patients by targeting MCM2 in the clinic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Gastric cancer (GC) is one of the most common malignant tumors of the digestive system. High expression of the mitotic kinase BUB1 has been shown to be associated with the development of many cancers, but the role of BUB1 in GC is still unclear. The current study aimed to investigate the role of BUB1 in GC., Materials and Methods: BUB1 inhibitor, siRNA or BUB1 overexpression plasmid-mediated functional studies were performed in vitro and in vivo to explore the oncogenic role of BUB1 in GC. The expression of BUB1 and FGF18 in GC tumor samples was determined by IHC staining. RNA-seq, Western blot, MeRIP-qPCR and Co-IP assays were used to investigate the molecular mechanisms by which BUB1 regulates GC progression., Key Findings: Knockdown of BUB1 significantly inhibited the proliferation and metastasis of GC cells in vitro and in vivo. Moreover, overexpression of BUB1 significantly promoted the proliferation, migration and invasion of GC cells. High expression of BUB1 and FGF18 in GC tissues predicted poor prognosis in GC patients. Mechanistically, BUB1 interacted with METTL3 and induced m6A modification of TRAF6 mRNA, further activating the NF-κB/FGF18 axis in GC cells., Significance: Our results confirmed that BUB1 acts as a positive regulator of GC cell proliferation and metastasis by activating the TRAF6/NF-κB/FGF18 pathway through METTL3-mediated m6A methylation. Targeting the BUB1/METTL3/TRAF6/NF-κB/FGF18 axis might be a novel diagnostic and therapeutic strategy in GC., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer., Main Methods: We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan., Key Findings: Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan., Significance: Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients., Competing Interests: Declaration of competing interest The authors declare there are no competing interests, and all authors consent to publish the data., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: While small extracellular vesicles (sEVs)-derived circular RNAs (circRNAs) have been emerged as significant players in cancer, the function and underlying mechanism of sEVs-derived circRNAs in anti-cancer immunity remain unclear., Methods: Gastric cancer (GC)-derived circRNAs were identified using RNA-seq data from GEO datasets and quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA immunoprecipitation, dual-luciferase assay, and bioinformatics analysis were performed to investigate the regulatory axis. Transwell assay, wound healing assay, cell counting kit-8 (CCK-8) assay, and xenograft models were used to evaluate its role in GC progression in vivo and in vitro. The delivery of specific circRNAs into sEVs were verified through electron microscopy, nanoparticle tracking analysis (NTA) and fuorescence in situ hybridization (FISH). Flow cytometric analysis and immunohistochemical staining were conducted to find out how specific circRNAs mediated CD8 +  T cell exhaustion and resistant to anti-programmed cell death 1 (PD-1) therapy., Results: We identified that circ_0001947, packaged by GC-derived sEVs, was obviously elevated in GC and was associated with poor clinical outcome. High circ0001947 level augmented the proliferation, migration, and invasion of GC cells. Mechanistically, circ0001947 sponged miR-661 and miR-671-5p to promote the expression of CD39, which further facilitated CD8 +  T cell exhaustion and immune resistance. Conversely, blocking circ_0001947 attenuated CD8 +  T cell exhaustion and increased the response to anti-PD-1 therapy., Conclusions: Our study manifested the therapeutic potential of targeting sEVs-transmitted circ_0001947 to prohibit CD8 +  T cell exhaustion and immune resistance in GC., (© 2024. The Author(s).)

ICVB-1042 is an oncolytic adenovirus containing modifications to enhance replication, lysis, and viral spreading in tumor cells. The anti-tumor activity, immune activation, tropism, selectivity, and mechanism of action were evaluated in preparation for a first-in-human study. ICVB-1042 was at least 100-fold more cytotoxic in A549 cells than in normal primary cells tested, demonstrating its high tumor selectivity and a low likelihood of targeting primary tissues. ICVB-1042 administered to mice intravenously or intratumorally was effective in reducing tumor burden. Its intravenous administration also inhibited tumor growth in orthotopic models. ICVB-1042 was well tolerated in mice compared to HAdV-C5 (Wt Ad5), with reduced liver sequestration, supporting safety of the drug for systemic delivery. These preclinical data demonstrating the safety and potency of ICVB-1042 for treatment of various solid tumors support the ongoing clinical investigation (NCT05904236)., (© 2024. The Author(s).)

The stiffness of human cancers may be correlated with their pathology, and can be used as a biomarker for diagnosis, malignancy prediction, molecular expression, and postoperative complications. Neurosurgeons perform tumor resection based on tactile sensations. However, it takes years of surgical experience to appropriately distinguish brain tumors from surrounding parenchymal tissue. Haptics is a technology related to the touch sensation. Haptic technology can amplify, transmit, record, and reproduce real sensations, and the physical properties (e.g., stiffness) of an object can be quantified. In the present study, glioblastoma (SF126-firefly luciferase-mCherry [FmC], U87-FmC, U251-FmC) and malignant meningioma (IOMM-Lee-FmC, HKBMM-FmC) cell lines were transplanted into nude mice, and the stiffness of tumors and normal brain tissues were measured using our newly developed surgical forceps equipped with haptic technology. We found that all five brain tumor tissues were stiffer than normal brain tissue (p < 0.001), and that brain tumor pathology (three types of glioblastomas, two types of malignant meningioma) was significantly stiffer than normal brain tissue (p < 0.001 for all). Our findings suggest that tissue stiffness may be a useful marker to distinguish brain tumors from surrounding parenchymal tissue during microsurgery, and that haptic forceps may help neurosurgeons to sense minute changes in tissue stiffness., (© 2024. The Author(s).)

Background: Long-term accumulation of misfolded proteins leads to endoplasmic reticulum (ER) stress in colorectal cancer (CRC). However, the precise pathways controlling the decision between survival and apoptosis in CRC are unclear. Therefore, in this study, we investigated the function and molecular mechanism of glucosidase I (GCS1) in regulating ER stress in CRC., Methods: A public database was used to confirm the expression level of GCS1 in CRC and normal tissues. Clinical samples from our center were used to confirm the mRNA and protein expression levels of GCS1. Cell proliferation, migration, invasion, and apoptosis assays revealed the biological role of GCS1. Immunohistochemical techniques were used to evaluate the expression of key proteins in subcutaneous implanted tumors in nude mice, which provided further evidence for the biological function of GCS1 in promoting cancer in vivo. The results of coimmunoprecipitation-mass spectrometry analysis and immunofluorescence colocalization analysis the interaction between GCS1 and GRP78. In addition, the mechanism of action of USP10, GRP78, and GCS1 at the post- translational level was investigated. Finally, a tissue microarray was used to examine the connection between GCS1 and GRP78 expression and intracellular localization of these proteins using immunohistochemistry and immunofluorescence., Results: The experimental results revealed that GCS1 was substantially expressed in CRC, with higher expression indicating a worse prognosis. Thus, GCS1 can enhance the proliferation and metastasis while inhibiting the apoptosis of CRC cells both in vivo and in vitro. Mechanistically, GCS1 binds to GRP78, recruits USP10 for deubiquitination of GRP78 to promote its degradation, and decreases ER stress-mediated apoptosis, increasing CRC cell proliferation and metastasis., Conclusions: In summary, GCS1 stimulates CRC growth and migration and reduces ER stress-mediated apoptosis via USP10-mediated deubiquitination of GRP78. Our findings identify a possible therapeutic target for CRC., (© 2024. The Author(s).)

Background: Zinc finger MIZ-type containing 2 (ZMIZ2) can function as a coactivator and participate in the progression of certain malignant tumors; however, its expression and underlying molecular mechanism in non-small-cell lung cancer (NSCLC) remains unknown. In this study, we aim to analyze the expression of ZMIZ2 and its tumorigenic function in NSCLC, identifying its related factors., Methods: ZMIZ2 expression in NSCLC tissue samples and cell lines was examined using immunohistochemistry and western blotting; its biological role was investigated using in vivo and in vitro assays. The association between ZMIZ2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was demonstrated using mass spectrometry and immunoprecipitation experiments. Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG)-based enrichment analysis, luciferase reporter assay, and real-time quantitative polymerase chain reaction (RT-qPCR) were conducted to verify the impact of ZMIZ2-SIRT1 combination on Hippo/Wnt pathways., Results: ZMIZ2 was highly expressed in NSCLC and positively associated with advanced pTNM staging, lymph node metastasis, and poor overall survival. Functional experiments revealed that ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells-establishing its role as a promoter of oncogenes. Molecular mechanism studies identified SIRT1 as an assisted key factor interacting with ZMIZ2. KEGG enrichment analysis revealed that ZMIZ2 is closely related to Wnt/Hippo pathways; ZMIZ2-SIRT1 interaction enhanced SIRT1 deacetylase activity. Direct downregulation of intranuclear β-catenin and yes-associated protein (YAP) acetylation levels occurred independently of upstream proteins in Wnt/Hippo pathways; transcriptional activities of β-catenin-transcription factor 4 (TCF4) and YAP-TEA domain family transcription factors (TEADs) were amplified., Conclusions: ZMIZ2 promotes the malignant phenotype of lung cancer by regulating Wnt/Hippo pathways through SIRT1, providing an experimental basis for discovering novel biomarkers and developing tumor-targeted drugs., (© 2024. The Author(s).)

The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where various activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds active KRAS, including mutant forms, competes with RAF and limits oncogenic KRAS downstream signalling, maintaining mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity at an optimal level. SHANK3 depletion breaches this threshold, triggering MAPK/ERK signalling hyperactivation and MAPK/ERK-dependent cell death in KRAS-mutant cancers. Targeting this vulnerability through RNA interference or nanobody-mediated disruption of the SHANK3-KRAS interaction constrains tumour growth in vivo in female mice. Thus, inhibition of SHANK3-KRAS interaction represents an alternative strategy for selective killing of KRAS-mutant cancer cells through excessive signalling., (© 2024. The Author(s).)

Cancer cells autonomously alter metabolic pathways in response to dynamic nutrient conditions in the microenvironment to maintain cell survival and proliferation. A better understanding of these adaptive alterations may reveal the vulnerabilities of cancer cells. Here, we demonstrate that coactivator-associated arginine methyltransferase 1 (CARM1) is frequently overexpressed in gastric cancer and predicts poor prognosis of patients with this cancer. Gastric cancer cells sense a reduced extracellular glucose content, leading to activation of nuclear factor erythroid 2-related factor 2 (NRF2). Subsequently, NRF2 mediates the classic antioxidant pathway to eliminate the accumulation of reactive oxygen species induced by low glucose. We found that NRF2 binds to the CARM1 promoter, upregulating its expression and triggering CARM1-mediated hypermethylation of histone H3 methylated at R arginine 17 (H3R17me2) in the glucose-6-phosphate dehydrogenase gene body. The upregulation of this dehydrogenase, driven by the H3R17me2 modification, redirects glucose carbon flux toward the pentose phosphate pathway. This redirection contributes to nucleotide synthesis (yielding nucleotide precursors, such as ribose-5-phosphate) and redox homeostasis and ultimately facilitates cancer cell survival and growth. NRF2 or CARM1 knockdown results in decreased H3R17me2a accompanied by the reduction of glucose-6-phosphate dehydrogenase under low glucose conditions. Collectively, this study reveals a significant role of CARM1 in regulating the tumor metabolic switch and identifies CARM1 as a potential therapeutic target for gastric cancer treatment., (© 2024. The Author(s).)

An increasing body of evidence suggests that acylphosphatase-2 (ACYP2) polymorphisms are correlated with an increased susceptibility to a range of malignancies. Nevertheless, its potential functions, molecular mechanisms in hepatocellular carcinoma (HCC) and whether it can be act as a therapeutic target remain uninvestigated. Herein, ACYP2 was found to be lowly expressed in HCC and was negatively correlated with tumor size, tumor differentiation, microvascular invasion and the prognosis of HCC patients. Functional investigations revealed that overexpression of ACYP2 inhibited the proliferation and metastasis of HCC cells while promoting apoptosis; knockdown of ACYP2 had the exact opposite effect. Additionally, it was observed that ACYP2 was distributed in both the cytoplasm and nucleus of HCC cells. According to the mechanistic studies, the expression of potassium calcium-activated channel subfamily N member 4 (KCNN4) was negatively regulated by cytoplasmic ACYP2, resulting in the inhibition of K + outflow and subsequent inactivation of the ERK pathway, which impeded the growth and metastasis of HCC. Furthermore, the activity of telomerase reverse transcriptase (TERT) was inhibited by nuclear ACYP2, leading to the reduction in length of telomeres and consequent reversal of HCC cell immortalization. Additionally, a novel targeted nanotherapy strategy was developed wherein the pcDNA-ACYP2 vector was encapsulated within polyetherimide nanoparticles (PEI/NPs), which were subsequently coated with HCC cell membranes (namely pcDNA/PEI/NPs@M). Safety and targeting characteristics abound for these nanocomposites, in both subcutaneous graft tumor models and orthotopic mouse models, they inhibited the progression of HCC by impeding TERT activity and the KCNN4/ERK pathway. In conclusion, our research identifies novel molecular mechanisms involving cytoplasmic and nuclear ACYP2 that inhibit the progression of HCC. Moreover, pcDNA/PEI/NPs@M represents a targeted therapeutic strategy for HCC that holds great promising., (© 2024. The Author(s).)

Breast cancer is the second primary cause of cancer death among women. Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is a central regulator for X chromosome inactivation, and its abnormal expression is a primary feature of breast cancer. So far, the mechanism of XIST in breast cancer has not been fully elucidated. We attempted to illustrate the mechanism of XIST in breast cancer. The expressions of XIST, microRNA-455-3p (miR-455-3p) in breast cancer were measured using quantitative real-time PCR. The expressions of homeobox C4 (HOXC4) were assessed with immunohistochemical and Western blot. Also, the functions of XIST in breast cancer were assessed by Cell Counting Kit-8 analysis, colony formation assay, flow cytometry, Western blot, Transwell, and cell scratch assays. Meanwhile, the mechanism of XIST in breast cancer was validated using database analysis and dual-luciferase reporter assay. Furthermore, the function of XIST in breast cancer in vivo was estimated by tumor xenograft model, immunohistochemical assay, and hematoxylin-eosin staining. XIST and HOXC4 expressions were increased, but miR-455-3p expressions were decreased in breast cancer tissues and cells. Knocking down XIST restrained breast cancer cell proliferation, invasion, migration, epithelial-mesenchymal transformation (EMT), and induced cell cycle arrest at G0/G1. Meanwhile, XIST interacted with miR-455-3p, while miR-455-3p interacted with HOXC4. XIST knockdown repressed breast cancer cell proliferation, invasion, and EMT, while miR-455-3p inhibitor or HOXC4 overexpression abolished those impacts. HOXC4 overexpression also blocked the impacts of miR-455-3p mimic on breast cancer cell malignant behavior. In vivo experimental data further indicated that XIST knockdown repressed breast cancer cell tumorigenic ability, and decreased HOXC4 and p-SMAD3 (TGF-β/SMAD-related protein) expressions.XIST/miR-455-3p/HOXC4 facilitated breast cancer development by activating the TGF-β/SMAD pathway., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hepatocellular carcinoma (LIHC) has severe consequences due to late diagnosis and the lack of effective therapies. Currently, potential biomarkers for the diagnosis and prognosis of LIHC have not been systematically evaluated. Previous studies have reported that RAC1 is associated with the B cell receptor signaling pathway in various tumor microenvironments, but its relationship with LIHC remains unclear. We investigated the relationship between RAC1 and the prognosis and immune infiltration microenvironment of LIHC, exploring its potential as a prognostic biomarker for this type of cancer., Methods: In this study, we analyzed data from The Cancer Genome Atlas (TCGA) using the Wilcoxon signed-rank test and logistic regression to assess the association between RAC1 expression and clinical characteristics in LIHC patients. Additionally, Kaplan-Meier and Cox regression methods were employed to confirm the impact of RAC1 expression levels on overall survival. Immunohistochemistry was used to validate RAC1 protein expression in LIHC. We constructed RAC1 knockdown LIHC cells and studied the effects of RAC1 protein on cell proliferation and migration at both cellular and animal levels., Results: RAC1 expression levels were significantly elevated in LIHC tissues compared to normal tissues. High RAC1 expression was strongly associated with advanced pathological stages and was identified as an independent factor negatively affecting overall survival. At both cellular and animal levels, RAC1 knockdown significantly inhibited the proliferation and migration of LIHC cells. Furthermore, RAC1 expression was positively correlated with the infiltration of Th2 cells and macrophages in the tumor microenvironment, suggesting that RAC1 may contribute to the deterioration of the tumor immunosuppressive microenvironment and potentially lead to reduced patient survival., Conclusion: These findings indicate that RAC1 expression promotes LIHC proliferation and migration and influences the landscape of immune cell infiltration in the tumor microenvironment. Based on these results, RAC1 is proposed as a potential prognostic biomarker for LIHC, associated with both cancer progression and tumor immune cell infiltration., (© 2024. The Author(s).)

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and STAT3 has emerged as an effective drug target for TNBC treatment. Herein, we employed a scaffold-hopping strategy of natural products to develop a series of naphthoquinone-furopiperidine derivatives as novel STAT3 inhibitors. The in vitro assay showed that compound 10g possessed higher antiproliferative activity than Cryptotanshinone and Napabucasin against TNBC cell lines, along with lower toxicity and potent antitumor activity in a TNBC xenograft model. Mechanistically, 10g could inhibit the phosphorylation of STAT3 and the binding affinity was determined by the SPR assay ( K D = 8.30 μM). Molecule docking studies suggested a plausible binding mode between 10g and the SH2 domain, in which the piperidine fragment and the terminal hydroxy group of 10g played an important role in demonstrating the success of this evolution strategy. These findings provide a natural product-inspired novel STAT3 inhibitor for TNBC treatment.

Given the extensive role of lipids in cancer development, there is substantial clinical interest in developing therapies that target lipid metabolism. In this study, we identified one cyclometalated iridium complex ( Ir2 ) that exhibits potent antiproliferation activity in MIA PaCa-2 cells by regulating fatty acid metabolism and sphingolipid metabolism simultaneously. Ir2 also efficiently overcomes cisplatin resistance in vitro . Satisfyingly, the generated Ir2@F127 carriers, as a temperature-sensitiv e in situ gelling system of Ir2 , showed effective cancer treatment with minimal side effects in an in vivo xenograft study. To the best of our knowledge, Ir2 is the first reported cyclometalated iridium complex that exerts anticancer activity in MIA PaCa-2 cells by intervening in lipid metabolism, which provides an alternative pathway for the anticancer mechanism of cyclometalated iridium complexes.

DNA N 6 -methyladenine (6mA) demethylase ALKBH1 plays an important role in various cellular processes. Dysregulation of ALKBH1 is associated with the development of some cancer types, including gastric cancer, implicating a potential therapeutic target. However, there is still a lack of potent ALKBH1 inhibitors. Herein, we report the discovery of a highly potent ALKBH1 inhibitor, 1 H -pyrazole-4-carboxylic acid derivative 29 . The structure-activity relationship of this series of compounds was also discussed. Because of the poor cell membrane permeability of 29 , we prepared a prodrug of 29 ( 29E ), which showed excellent cellular activities. In gastric cancer cell lines HGC27 and AGS, 29E treatment significantly increased the abundance of 6mA, inhibited cell viability, and upregulated the AMP-activated protein kinase (AMPK) signaling pathway. In addition, the hydrolysis product 29 showed high exposure in mice after administration of 29E . Collectively, this research provides a new potent ALKBH1 inhibitor, which could serve as a lead compound for subsequent drug development.

eEF2K, an atypical alpha-kinase, is responsible for regulating protein synthesis and energy homeostasis. Aberrant eEF2K function has been linked to various human cancers, including triple-negative breast cancer (TNBC). However, limited cellular activity of current eEF2K modulators impedes their clinical application. Based on the 2-phenyl-1,2,4-triazine-3,5(2 H ,4 H )-dione scaffold of our hits I4 and C1 , structure-activity relationship analysis led to the discovery of several more active derivatives (e.g., 19 , 34 , and 36 ) in inhibiting the viability of TNBC cell line MDA-MB-231. Moreover, the most potent compound 36 significantly suppresses the viability, proliferation, and migration of both MDA-MB-231 and HCC1806 cell lines. Mechanistically, compound 36 has a high binding affinity for the eEF2K protein and effectively induces its degradation. Additionally, 36 exerts a comparable tumor-suppressive effect to paclitaxel in an MDA-MB-231 cell xenograft mouse model with no obvious toxicity, demonstrating that compound 36 could be developed as a potential novel therapeutic for TNBC treatment.

As histone modification enzymes, EZH2 mediates H3K27 trimethylation (H3K27me3), whereas LSD1 removes methyl groups from H3K4me1/2 and H3K9me1/2. Synergistic anticancer effects of combining inhibitors of these two enzymes are observed in leukemia and prostate cancer. Thus, a series of EZH2/LSD1 dual inhibitors are designed and synthesized to evaluate their anticancer activity. After the structure-activity study, one of the best compounds, ML234 , displayed excellent antiproliferative capacity against prostate cancer cell lines LNCAP, PC3, and 22RV1. Enzymatic assays ascertained that the anticancer potency of ML234 was mediated through coinhibition of EZH2 and LSD1. Moreover, the accumulation of H3K4me2 and H3K9me2 and the decrease of H3K27me3 induced by ML234 were verified by Western blot analysis. More importantly, the compound remarkably suppressed the tumor growth and enhanced the therapeutic efficacy of clinical drug enzalutamide in the 22RV1 xenograft mouse model, indicating that it may have potential as an anticancer agent in prostate cancer.

The serine/threonine phosphatase family is important in tumor progression and survival. Due to the high conserved catalytic domain, designing selective inhibitors is challenging. Herein, we obtained compound 28a with 38-fold enhanced PP5 selectivity (PP2A/5 IC 50 = 33.8/0.9 μM) and improved drug-like properties (favorable stability and safety, F = 82.0%) by rational drug design based on a phase II PP2A/5 dual target inhibitor LB-100 . Importantly, we found the spatial conformational restriction of the 28a indole fragment was responsible for the selectivity of PP5. Thus, 28a activated p53 and downregulated cyclin D1 and MGMT, which showed potency in cell cycle arrest and reverse temozolomide (TMZ) resistance in the U87 MG cell line. Furthermore, oral administration of 28a and TMZ was well tolerated to effectively inhibit tumor growth (TGI = 87.7%) in the xenograft model. Collectively, these results implicate 28a could be a drug candidate by reversing TMZ resistance with a selective PP5 inhibition manner.

As an obstinate cancer pancreatic cancer (PC) poses a major challenge due to limited treatment options which include resection surgery, radiation therapy, and gemcitabine-based chemotherapy. In cancer cells, protein kinase C βI (PKCβI) participates in diverse cellular processes, including cell proliferation, invasion, and apoptotic pathways. In the present study, we created a scaffold to develop PKCβI inhibitors using evodiamine-based synthetic molecules. Among the candidate inhibitors, Evo312 exhibited the highest antiproliferative efficacy against PC cells, PANC-1, and acquired gemcitabine-resistant PC cells, PANC-GR. Additionally, Evo312 robustly inhibited PKCβI activity. Mechanistically, Evo312 effectively suppressed the upregulation of PKCβI protein expression, leading to the induction of cell cycle arrest and apoptosis in PANC-GR cells. Furthermore, Evo312 exerted an antitumor activity in a PANC-GR cell-implanted xenograft mouse model. These findings position Evo312 as a promising lead compound for overcoming gemcitabine resistance in PC through novel mechanisms.

Mixed lineage kinase domain-like pseudokinase (MLKL) initiates necroptosis and could serve as a therapeutic target related to a series of human diseases. Proteolysis-targeting chimeras (PROTACs) are useful tools for degrading pathological proteins and blocking disease processes. Using computer-aided modeling and molecular dynamics simulations, we developed a series of covalent MLKL PROTACs by linking and optimizing a theophylline derivative that covalently targets MLKL. Via structure-activity relationship studies, MP-11 was identified as a potent MLKL PROTAC degrader. Furthermore, MP-11 showed lower toxicity than the original MLKL ligand, exhibiting nanomolar-scale antinecroptotic activity on human cell lines. Xenograft model studies showed that MP-11 effectively degraded MLKL in vivo. Importantly, our study demonstrates that the covalent binding strategy is an effective approach for designing MLKL-targeting PROTACs, serving as a model for developing PROTACs to treat future necroptosis-related human diseases.

Yes-associated protein (YAP) is a key oncogene in the Hippo tumor suppression pathway, historically challenging to target due to its intrinsically disordered nature. Leveraging recent advances in high-throughput screening that identified several YAP binders, we employed proteolysis-targeting chimera technology to develop a series of YAP degraders. Utilizing NSC682769, a known YAP binder, linked with VHL ligand 2 or pomalidomide via diverse linkers, we synthesized degraders including YZ-6 . This degrader not only recruits the E3 ligase VHL for the rapid and sustained degradation of YAP but also effectively inhibits its nuclear localization, curtailing YAP/TEAD-mediated transcription in cancer cell lines such as NCI-H226 and Huh7. This dual action significantly diminishes YAP's oncogenic activity, contributing to the potent antiproliferative effects observed both in vitro and in a Huh7 xenograft mouse model. These results underscore the potential of PROTAC-mediated YAP degradation as a strategy for treating YAP-driven cancers.

Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC 50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T / C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC 50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.

Based on the founding member of imipridones, ONC201 , a class of dehydrogenated imipridone derivatives was designed, synthesized, and evaluated in a series of biochemical and biological assays as human caseinolytic protease P (hClpP) activators. Mechanism studies for one of the most potent compounds, XT6 , indicated that it can potently bind to both recombinant and cellular hClpP, effectively promote the formation of hClpP tetradecamer, efficiently induce the degradation of hClpP substrates, robustly upregulate the expression of ATF4, and strongly inhibit the phosphorylations of AKT and ERK. More importantly, XT6 exhibited a promising pharmacokinetic profile in rats and could penetrate the blood brain barrier. It showed highly potent in vivo antitumor activity in a MIAPACA2 cell line derived pancreatic cancer model in BALB/c nude mice.

In this work, various novel pyridinyl- and pyridinium-modified Aza-BODIPY PSs were designed and constructed based on monoiodo Aza-BODIPY PSs ( BDP-4 and BDP-15 ) in an attempt to construct "structure-inherent organelles-targeted" PSs to endow potential organelle-targeting ability. Pyridinyl PSs displayed potent photodynamic efficacy, and monorigidified PSs were very effective. The monorigidified PS 20 with meta -pyridinyl moiety displayed the most potent photoactivity and negligible dark toxicity with a favorable dark/phototoxicity ratio (>4800). To our surprise, monorigidified PS with meta -pyridinyl moiety (e.g., 20 ) was lipid droplet-targeted. 20 showed good cellular uptake and intracellular ROS generation compared with BDP-15 . The preliminary cell death process exploration indicated that 20 resulted in lipid peroxidation and induced cell death through an iron-independent ferroptosis-like cell death pathway. In vivo antitumor efficacy experiments manifested that 20 significantly inhibited tumor growth and outperformed BDP-15 and Ce6 even under a single low-dose light irradiation (30 J/cm 2 ).

18 F-2-fluoro-2-deoxy-d-glucose ([ 18 F]FDG) has been the most used positron emission tomography imaging agent for clinical applications. Single photon emission computed tomography (SPECT) imaging is cheaper and used more widely for diagnostic use, but there is no SPECT tumor imaging agent for clinical applications comparable to [ 18 F]FDG. Mannose is a C2 epimer of glucose and can also be transported into tumor cells via glucose transporters (GLUTs). To develop a novel SPECT tumor imaging agent with satisfactory tumor uptake and tumor/nontarget ratios, here a mannose derivative (CN7DM) was synthesized and radiolabeled with technetium-99m to prepare [ 99m Tc]Tc-CN7DM. The six-coordinated structure of [ 99m Tc]Tc-CN7DM was confirmed by the corresponding rhenium compound (Re-CN7DM). [ 99m Tc]Tc-CN7DM was transported into cancer cells via GLUTs and may be trapped in the cancer cells by electrostatic attraction. The probe exhibited high uptake in tumors and low uptake in nontarget tissues in mice bearing different tumors, indicating that [ 99m Tc]Tc-CN7DM exhibited promising potential for SPECT tumor imaging and warranted further clinical investigation.

Herein, we described the rational drug design and synthesis of a series of 5-amino-4-fluoro-1 H -benzo[ d ]imidazole-6-carboxamide derivatives that inhibit MEK and RAF kinases. The detailed screening cascades revealed that 16b was a preferred compound, which might act like a "clamp" to stabilize the MEK/RAF complex, thereby effectively inhibiting MEK1, BRAF, and BRAF V600E with IC 50 values of 28, 3, and 3 nM, respectively. 16b possessed an excellent selectivity over other 312 human-related kinases at 1 μM. In vitro, 16b showed potent antiproliferative activities against MIA PaCa-2 (G12C KRAS), HCT116 (G13D KRAS), and C26 (G12D KRAS) cells with IC 50 values of 0.011, 0.079, and 0.096 μM, respectively. CoIP experiments demonstrated that 16b could induce MEK/RAF complex formation. Most importantly, in the C26 syngeneic colorectal and HCT116 mice xenograft tumor models, 16b demonstrated tumor growth inhibition of 70 and 93%, respectively, suggesting that 16b may be a promising MEK/RAF complex inhibitor and worthy of further development.

Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). Our lead compound, CAM2602 , inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.

Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is widely used in the clinical treatment of tumors. This study aims to explore the active fractions and underlying mechanisms of Fuzi in the treatment of non-small cell lung cancer (NSCLC). Fuzi alkaloids (FZA) is prepared and found to inhibit the growth of NSCLC both in vitro and in vivo significantly. A total of 53 alkaloids are identified in FZA by UPLC-Q-TOF-MS. Proteomics experiment show that 238 differentially expressed proteins regulated by FZA are involved in amino acid anabolism, pyrimidine metabolism and PI3K/Akt-mTOR signaling pathway. Metabolomics analyses identify 32 significant differential metabolites which are mainly involved in amino acid metabolism, TCA cycle and other pathways. Multi-omics research combined with molecular biological assays suggest that FZA might regulate glycolysis through PI3K/Akt-mTOR pathway to treat NSCLC. The study lays a foundation for the anti-cancer investigation of Fuzi and provides a possible scientific basis for its clinical application., (© 2024. The Author(s).)

Background: Cervical cancer, encompassing squamous cell carcinoma and endocervical adenocarcinoma (CESC), presents a considerable risk to the well-being of women. Recent studies have reported that squalene epoxidase (SQLE) is overexpressed in several cancers, which contributes to cancer development., Methods: RNA sequencing data for SQLE were obtained from The Cancer Genome Atlas. In vitro experiments, including colorimetry, colony formation, Transwell, RT-qPCR, and Western blotting were performed. Furthermore, a transplanted CESC nude mouse model was constructed to validate the tumorigenic activity of SQLE in vivo. Associations among the SQLE expression profiles, differentially expressed genes (DEGs), immune infiltration, and chemosensitivity were examined. The prognostic value of genetic changes and DNA methylation in SQLE were also assessed., Results: SQLE mRNA expression was significantly increased in CESC. ROC analysis revealed the strong diagnostic ability of SQLE toward CESC. Patients with high SQLE expression experienced shorter overall survival. The promotional effects of SQLE on cancer cell proliferation, metastasis, cholesterol synthesis, and EMT were emphasized. DEGs functional enrichment analysis revealed the signaling pathways and biological processes. Notably, a connection existed between the SQLE expression and the presence of immune cells as well as the activation of immune checkpoints. Increased SQLE expressions exhibited increased chemotherapeutic responses. SQLE methylation status was significantly associated with CESC prognosis., Conclusion: SQLE significantly affects CESC prognosis, malignant behavior, cholesterol synthesis, EMT, and immune infiltration; thereby offering diagnostic and indicator roles in CESC. Thus, SQLE can be a novel therapeutic target in CESC treatment., (© 2024. The Author(s).)

LHPP, a novel, recognized tumor suppressor, exerts a critical influence on the regulation of tumor cell proliferation and survival by modulating various signaling pathways with its phosphatase activity. Here, we unveil a robust correlation between reduced LHPP expression and adverse prognosis in prostate cancer. We demonstrate that LHPP interacts with AKT, thereby dampening AKT phosphorylation and subsequently inhibiting ACSL4 phosphorylation at the T624 site. This interaction impedes phosphorylation-dependent ubiquitination, thwarting SKP2 from recognizing and binding to ACSL4 at the K621 site. As a result, ACSL4 is spared from lysosomal degradation, leading to its accumulation and the promotion of lipid peroxidation, and ferroptosis. Moreover, our findings reveal that Panobinostat, a potent histone-deacetylase inhibitor, intricately regulates LHPP expression at multiple levels through the inhibition of HDAC3. This complex modulation enhances the ferroptosis pathway, offering a novel mechanism for curtailing the growth of prostate tumors and highlighting its significant translational potential for clinical application., (© 2024. The Author(s).)

Ovarian cancer is an extremely malignant gynaecological tumour with a poor patient prognosis and is often associated with chemoresistance. Thus, exploring new therapeutic approaches to improving tumour chemosensitivity is important. The expression of transcription elongation factor B polypeptide 2 (TCEB2) gene is reportedly upregulated in ovarian cancer tumour tissues with acquired resistance, but the specific mechanism involved in tumour resistance remains unclear. In this study, we found that TCEB2 was abnormally highly expressed in cisplatin-resistant tumour tissues and cells. TCEB2 silencing also inhibited the growth and glycolysis of SKOV-3/cisplatin (DDP) and A2780/DDP cells. We further incubated human umbilical vein endothelial cells (HUVECs) with culture supernatants from cisplatin-resistant cells having TCEB2 knockdown. Results revealed that the migration, invasion, and angiogenesis of HUVECs were significantly inhibited. Online bioinformatics analysis revealed that the hypoxia-inducible factor-1A (HIF-1A) protein may bind to TCEB2, and TCEB2 silencing inhibited SKOV-3/DDP cell growth and glycolysis by downregulating HIF1A expression. Similarly, TCEB2 promoted HUVEC migration, invasion, and angiogenesis by upregulating HIF1A expression. In vivo experiments showed that TCEB2 silencing enhanced the sensitivity of ovarian cancer nude mice to cisplatin and that TCEB2 knockdown inhibited the glycolysis and angiogenesis of tumour cells. Our findings can serve as a reference for treating chemoresistant ovarian cancer., (© 2024. The Author(s).)

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Although CRC patients' survival is improved with surgical resection and immunotherapy, metastasis and recurrence remain major problems leading to poor prognosis. Therefore, exploring pathogenesis and identifying specific biomarkers are crucial for CRC early diagnosis and targeted therapy. CCDC113, a member of CCDC families, has been reported to play roles in ciliary assembly, ciliary activity, PSCI, asthma and early lung cancer diagnosis. However, the functions of CCDC113 in CRC still remain unclear. In this study, we find that CCDC113 is significantly highly expressed in CRC. High expression of CCDC113 is significantly correlated with CRC patients' poor prognosis. CCDC113 is required for CRC tumorigenesis and metastasis. RNA-seq and TCGA database analysis indicate that CCDC113 is positively correlated with TGF-β signaling pathway. TGF-β signaling pathway inhibitor galunisertib could reverse the increased proliferation and migration ability of CRC cells caused by CCDC113 overexpression in vitro and in vivo. These results indicate that CCDC113 promotes CRC tumorigenesis and metastasis via TGF-β signaling pathway. In conclusion, it is the first time to explore the functions and mechanisms of CCDC113 in CRC tumorigenesis and metastasis. And CCDC113 may be a potential biomarker and therapeutic target for CRC intervention., (© 2024. The Author(s).)

Surgical resection remains the main treatment for malignant tumors. Image-guided surgery aims to remove tumor tissue completely while preserving normal tissue, thereby reducing tumor recurrence rates and injury. However, challenges like tissue autofluorescence, limited probe penetration and low contrast restrict its use. Near-infrared (NIR) persistent luminescent nanoparticles (PLNPs) provide a solution by emitting persistent luminescence (PersL) even after excitation ceases, thus circumventing autofluorescence and enabling deep tumor imaging. In this study, we prepared nano-sized (140 nm hydrodynamic size) Cr 3+ doped zinc gallogermanate (ZGC) using a removable template method and modified it with folate acid to obtain ZGC-FA, which exhibits NIR (695 nm) PersL with a signal-to-noise ratio of 23.9 in vivo . We utilized a colon cancer model that selectively expressed luciferase for the first time to validate the guiding efficacy of ZGC-FA in precision surgical resection. Post-intraperitoneal injection at 50 minutes, the PersL closely matched the tumor boundaries, achieving an overlap rate of approximately 98%. Complete tumor resection was achieved under PersL guidance, with only 2.3% of healthy tissue removed. This research underscores the potential of ZGC-FA in the field of surgical oncology. The precision of the ZGC-FA guided surgical approach holds promise to enhance surgical outcomes and facilitate postoperative recovery in patients.

With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.

Laryngeal cancer (LC) is the second most common head and neck cancer and has a decreasing 5-year survival rate worldwide. Circular RNAs (circRNAs) regulate cancer development in diverse ways based on their distinct biogenesis mechanisms and expansive regulatory roles. However, currently, there is little research on how exosomal circRNAs are involved in the development of LC. Here, we demonstrated that circPVT1, a circRNA derived from the well-studied long noncoding RNA PVT1, is correlated with disease progression in LC and promotes angiogenesis both in vivo and in vitro. Mechanistically, circPVT1 is loaded into LC cell-secreted exosomes and taken up by vascular epithelium cells. By sponging miR-30c-5p, exosomal circPVT1 promotes Rap1b expression, which dramatically enhances vascular endothelial growth factor receptor 2 and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation, ultimately resulting in the induction of angiogenesis. Furthermore, our xenograft models demonstrated that the combination of short hairpin RNA-circPVT1 and cetuximab showed high efficacy in inhibiting tumor growth and angiogenesis. Collectively, these findings uncover a novel mechanism of exosomal circRNA-mediated angiogenesis modulation and provide a preclinical rationale for testing this analogous combination in patients with LC., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Herein, we developed a paclitaxel prodrug (PSFc) through the conjugation of paclitaxel (PTX) and ferrocene via a redox-responsive disulfide bond. PSFc displays acid-enhanced catalytic activity of Fenton reaction and is capable of forming stable nanoparticles (PSFc NPs) through the assembly with distearoyl phosphoethanolamine-PEG 2000 . After being endocytosed, PSFc NPs could release PTX to promote cell apoptosis in response to overexpressed redox-active species of tumor cells. Meanwhile, the ferrocene-mediated Fenton reaction promotes intracellular accumulation of hydroxyl radicals and depletion of glutathione, thus leading to ferroptosis. Compared with the clinically used Taxol, PSFc NPs exhibited more potent in vivo antitumor outcomes through the combined effect of chemotherapy and ferroptosis. This study may offer insight into a facile design of a prodrug integrating different tumor treatment methods for combating malignant tumors.

Long noncoding RNA urothelial carcinoma-associated 1 (UCA1) has been implicated in several tumors. UCA1 promotes cell proliferation, migration, and invasion of gastric cancer (GC) cells, but the molecular mechanism has not been fully elucidated. This study revealed the oncogenic effects of UCA1 on cell growth and invasion. Furthermore, UCA1 expression was significantly correlated with the overall survival of GC patients, and the clinicopathological indicators, including tumor size, depth of invasion, lymph node metastasis, and TNM stage. Additionally, miR-1-3p was identified as a downstream target of UCA1, which was negatively regulated by UCA1. MiR-1-3p inhibited cell proliferation and vasculogenic mimicry (VM), and induced cell apoptosis by upregulating BAX, BAD, and tumor suppressor TP53 expression levels. Moreover, miR-1-3p almost completely reversed the oncogenic effect caused by UCA1, including cell growth, migration, and VM formation. This study also confirmed that UCA1 promoted tumor growth in vivo. In this study, we also revealed the correlation between UCA1 and VM formation, which is potentially crucial for tumor metastasis. Meanwhile, its downstream target miR-1-3p inhibited VM formation in GC cells. In summary, these findings indicate that the UCA1/miR-1-3p axis is a potential target for GC treatment., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)