Search

Each tRNA is aminoacylated (charged) with a genetic codon‐specific amino acid. It remains unclear what factors are associated with tRNA charging and how tRNA charging is maintained. By using the individual tRNA acylation PCR method, we found that the charging ratio of tRNAGln(CUG) reflects cellular glutamine level. When uncharged tRNAGln(CUG) increased under amino acid starvation, the kinase GCN2, which is a key stimulator of the integrated stress response, was activated. Activation of GCN2 led to the upregulation of ubiquitin C (UBC) expression. Upregulated UBC, in turn, suppressed the further reduction in tRNAGln(CUG) charging levels. Thus, tRNA charging is sensitive to intracellular nutrient status and is an important initiator of intracellular signaling. [ABSTRACT FROM AUTHOR]

Virilizer-like m6A methyltransferase-associated protein (VIRMA) maintains the stability of the m6A writer complex. Although VIRMA is critical for RNA m6A deposition, the impact of aberrant VIRMA expression in human diseases remains unclear. We show that VIRMA is amplified and overexpressed in 15–20% of breast cancers. Of the two known VIRMA isoforms, the nuclear-enriched full-length but not the cytoplasmic-localised N-terminal VIRMA promotes m6A-dependent breast tumourigenesis in vitro and in vivo. Mechanistically, we reveal that VIRMA overexpression upregulates the m6A-modified long non-coding RNA, NEAT1, which contributes to breast cancer cell growth. We also show that VIRMA overexpression enriches m6A on transcripts that regulate the unfolded protein response (UPR) pathway but does not promote their translation to activate the UPR under optimal growth conditions. Under stressful conditions that are often present in tumour microenvironments, VIRMA-overexpressing cells display enhanced UPR and increased susceptibility to death. Our study identifies oncogenic VIRMA overexpression as a vulnerability that may be exploited for cancer therapy. [ABSTRACT FROM AUTHOR]

Precise regulation of mRNA translation is of fundamental importance for maintaining homeostasis. Conversely, dysregulated general or transcript-specific translation, as well as abnormal translation events, have been linked to a multitude of diseases. However, driven by the misconception that the transient nature of mRNAs renders their abnormalities inconsequential, the importance of mechanisms that monitor the quality and fidelity of the translation process has been largely overlooked. In recent years, there has been a dramatic shift in this paradigm, evidenced by several seminal discoveries on the role of a key mechanism in monitoring the quality of mRNA translation - namely, Ribosome Quality Control (RQC) - in the maintenance of homeostasis and the prevention of diseases. Here, we will review recent advances in the field and emphasize the biological significance of the RQC mechanism, particularly its implications in human diseases., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: Free water in cortical bone is either contained in nearly cylindrical structures (mainly Haversian canals oriented parallel to the bone axis) or in more spherically shaped pores (lacunae). Those cavities have been reported to crucially influence bone quality and mechanical stability. Susceptibility differences between bone and water can lead to water frequency shifts dependent on the geometric characteristics. The purpose of this study is to calculate and measure the frequency distribution of the water signal in MRI in dependence of the microscopic bone geometry., Methods: Finite element modeling and analytical approaches were performed to characterize the free water components of bone. The previously introduced UTE-FID technique providing spatially resolved FID-spectra was used to measure the frequency distribution pixel-wise for different orientations of the bone axis., Results: The frequency difference between free water in spherical pores and in canals parallel to B 0 amounts up to approximately 100 Hz at 3T. Simulated resonance frequencies showed good agreement with the findings in UTE-FID spectra. The intensity ratio of the two signal components (parallel canals and spherical pores) was found to vary between periosteal and endosteal regions., Conclusion: Spatially resolved UTE-FID examinations allow the determination of the frequency distribution of signals from free water in cortical bone. This frequency distribution indicates the composition of the signal contributions from nearly spherical cavities and cylindrical canals which allows for further characterization of bone structure and status., (© 2024 International Society for Magnetic Resonance in Medicine.)

Autophagy is a cytoplasmic defense mechanism that cells use to break and reprocess their intracellular components. This utilization of autophagy is regarded as a savior in nutrient-deficient and other stressful conditions. Hence, autophagy keeps contact with and responds to miscellaneous cellular tensions and diverse pathways of signal transductions, such as growth signaling and cellular death. Importantly, autophagy is regarded as an effective tumor suppressor because regular autophagic breakdown is essential for cellular maintenance and minimizing cellular damage. However, paradoxically, autophagy has also been observed to promote the events of malignancies. This review discussed the dual role of autophagy in cancer, emphasizing its influence on tumor survival and progression. Possessing such a dual contribution to the malignant establishment, the prevention of autophagy can potentially advocate for the advancement of malignant transformation. In contrast, for the context of the instituted tumor, the agents of preventing autophagy potently inhibit the advancement of the tumor. Key regulators, including calpain 1, mTORC1, and AMPK, modulate autophagy in response to nutritional conditions and stress. Oncogenic mutations like RAS and B-RAF underscore autophagy's pivotal role in cancer development. The review also delves into autophagy's context-dependent roles in tumorigenesis, metastasis, and the tumor microenvironment (TME). It also discusses the therapeutic effectiveness of autophagy for several cancers. The recent implication of autophagy in the control of both innate and antibody-mediated immune systems made it a center of attention to evaluating its role concerning tumor antigens and treatments of cancer., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Asparagine is a non-essential amino acid crucial for protein biosynthesis and function, and therefore cell maintenance and growth. Furthermore, this amino acid has an important role in regulating several metabolic pathways, such as tricarboxylic acid cycle and the urea cycle. When compared to normal cells, tumor cells typically present a higher demand for asparagine, making it a compelling target for therapy. In this review article, we investigate different facets of asparagine bioavailability intricate role in malignant tumors raised from solid organs. We take a comprehensive look at asparagine synthetase expression and regulation in cancer, including the impact on tumor growth and metastasis. Moreover, we explore asparagine depletion through L-asparaginase as a potential therapeutic method for aggressive solid tumors, approaching different formulations of the enzyme and combinatory therapies. In summary, here we delve into studies about endogenous and exogenous asparagine availability in solid cancers, analyzing therapeutic implications and future challenges., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The integrated stress response (ISR) triggered in response to various cellular stress enables mammalian cells to effectively cope with diverse stressful conditions while maintaining their normal functions. Four kinases (PERK, PKR, GCN2, and HRI) of ISR regulate ISR signaling and intracellular protein translation via mediating the phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α) at Ser51. Early ISR creates an opportunity for cells to repair themselves and restore homeostasis. This effect, however, is reversed in the late stages of ISR. Currently, some studies have shown the non-negligible impact of ISR on diseases such as ischemic diseases, cognitive impairment, metabolic syndrome, cancer, vanishing white matter, etc. Hence, artificial regulation of ISR and its signaling with ISR modulators becomes a promising therapeutic strategy for relieving disease symptoms and improving clinical outcomes. Here, we provide an overview of the essential mechanisms of ISR and describe the ISR-related pathways in organelles including mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. Meanwhile, the regulatory effects of ISR modulators and their potential application in various diseases are also enumerated., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Cellular senescence is a state of durable cell arrest that has been identified both in vitro and in vivo. It is associated with profound changes in gene expression and a specific secretory profile that includes pro-inflammatory cytokines, growth factors and matrix-remodelling enzymes, referred to as the senescence-associated secretory phenotype (SASP). In cancer, senescence can have anti- or pro-tumour effects. On one hand, it can inhibit tumour progression in a cell autonomous manner. On the other hand, senescence can also promote tumour initiation, progression, metastatic dissemination and resistance to therapy in a paracrine manner. Therefore, despite efforts to target senescence as a potential strategy to inhibit tumour growth, senescent cancer and microenvironmental cells can eventually lead to uncontrolled proliferation and aggressive tumour phenotypes. This can happen either through overcoming senescence growth arrest or through SASP-mediated effects in adjacent tumour cells. This review will discuss how senescence affects the tumour microenvironment, including extracellular matrix remodelling, the immune system and the vascular compartment, to promote tumourigenesis, metastasis and resistance to DNA-damaging therapies. It will also discuss current approaches used in the field to target senescence: senolytics, improving the immune clearance of senescent cells and targeting the SASP., (© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor patient prognosis. Remarkably, PDAC is one of the most aggressive and deadly tumor types and is notorious for its resistance to all types of treatment. PDAC resistance is frequently associated with a wide metabolic rewiring and in particular of the glycolytic branch named Hexosamine Biosynthetic Pathway (HBP). Methods: Transcriptional and bioinformatics analysis were performed to obtain information about the effect of the HBP inhibition in two cell models of PDAC. Cell count, western blot, HPLC and metabolomics analyses were used to determine the impact of the combined treatment between an HBP's Phosphoglucomutase 3 (PGM3) enzyme inhibitor, named FR054, and erastin (ERA), a recognized ferroptosis inducer, on PDAC cell growth and survival. Results: Here we show that the combined treatment applied to different PDAC cell lines induces a significant decrease in cell proliferation and a concurrent enhancement of cell death. Furthermore, we show that this combined treatment induces Unfolded Protein Response (UPR), NFE2 Like BZIP Transcription Factor 2 (NRF2) activation, a change in cellular redox state, a greater sensitivity to oxidative stress, a major dependence on glutamine metabolism, and finally ferroptosis cell death. Conclusion: Our study discloses that HBP inhibition enhances, via UPR activation, the ERA effect and therefore might be a novel anticancer mechanism to be exploited as PDAC therapy. [ABSTRACT FROM AUTHOR]

Immune suppressive factors of the tumor microenvironment (TME) undermine viability and exhaust the activities of the intratumoral cytotoxic CD8 + T lymphocytes (CTL) thereby evading anti-tumor immunity and decreasing the benefits of immune therapies. To counteract this suppression and improve the efficacy of therapeutic regimens, it is important to identify and understand the critical regulators within CD8 + T cells that respond to TME stress and tumor-derived factors. Here we investigated the regulation and importance of activating transcription factor-4 (ATF4) in CTL using a novel Atf4ΔCD8 mouse model lacking ATF4 specifically in CD8 + cells. Induction of ATF4 in CD8 + T cells occurred in response to antigenic stimulation and was further increased by exposure to tumor-derived factors and TME conditions. Under these conditions, ATF4 played a critical role in the maintenance of survival and activities of CD8 + T cells. Conversely, selective ablation of ATF4 in CD8 + T cells in mice rendered these Atf4ΔCD8 hosts prone to accelerated growth of implanted tumors. Intratumoral ATF4-deficient CD8 + T cells were under-represented compared to wild-type counterparts and exhibited impaired activation and increased apoptosis. These findings identify ATF4 as an important regulator of viability and activity of CD8 + T cells in the TME and argue for caution in using agents that could undermine these functions of ATF4 for anti-cancer therapies. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) has been extensively investigated; however, it is complex and remains unclear, especially in elderly patients. Senescence is a cellular response to a variety of stress signals, which is characterized by stable arrest of the cell cycle and major changes in cell morphology and physiology. To the best of our knowledge, senescence leads to consistent arrest of tumor cells and remodeling of the tumor-immune microenvironment (TIME) by activating a set of pleiotropic cytokines, chemokines, growth factors, and proteinases, which constitute the senescence-associated secretory phenotype (SASP). On the one hand, the SASP promotes antitumor immunity, which enhances treatment efficacy; on the other hand, the SASP increases immunosuppressive cell infiltration, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), M2 macrophages, and N2 neutrophils, contributing to TIME suppression. Therefore, a deeper understanding of the regulation of the SASP and components contributing to robust antitumor immunity in elderly individuals with different cancer types and the available therapies is necessary to control tumor cell senescence and provide greater clinical benefits to patients. In this review, we summarize the key biological functions mediated by cytokines and intercellular interactions and significant components of the TME landscape, which influence the immunotherapy response in geriatric oncology. Furthermore, we summarize recent advances in clinical practices targeting TME components and discuss potential senescent TME targets. [ABSTRACT FROM AUTHOR]

Macrophages are the preeminent phagocytic cells which control multiple infections. Tuberculosis a leading cause of death in mankind and the causative organism Mycobacterium tuberculosis (MTB) infects and persists in macrophages. Macrophages use reactive oxygen and nitrogen species (ROS/RNS) and autophagy to kill and degrade microbes including MTB. Glucose metabolism regulates the macrophage-mediated antimicrobial mechanisms. Whereas glucose is essential for the growth of cells in immune cells, glucose metabolism and its downsteam metabolic pathways generate key mediators which are essential co-substrates for post-translational modifications of histone proteins, which in turn, epigenetically regulate gene expression. Herein, we describe the role of sirtuins which are NAD+-dependent histone histone/protein deacetylases during the epigenetic regulation of autophagy, the production of ROS/RNS, acetyl-CoA, NAD+, and Sadenosine methionine (SAM), and illustrate the cross-talk between immunometabolism and epigenetics on macrophage activation. We highlight sirtuins as emerging therapeutic targets for modifying immunometabolism to alter macrophage phenotype and antimicrobial function. [ABSTRACT FROM AUTHOR]

Lactation is a physiological adaptation of the class Mammalia and is a product of over 200 million years of evolution. During lactation, the mammary gland orchestrates bone metabolism via serotonin signaling in order to provide sufficient calcium for the offspring in milk. The role of serotonin in bone remodeling was first discovered over two decades ago, and the interplay between serotonin, lactation, and bone metabolism has been explored in the years following. It is estimated that postpartum depression affects 10–15% of the population, and selective serotonin reuptake inhibitors (SSRI) are often used as the first-line treatment. Studies conducted in humans, nonhuman primates, sheep, and rodents have provided evidence that there are consequences on both parent and offspring when serotonin signaling is disrupted during the peripartal period; however, the long-term consequences of disruption of serotonin signaling via SSRIs during the peripartal period on the maternal and offspring skeleton are not fully known. This review will focus on the relationship between the mammary gland, serotonin, and bone remodeling during the peripartal period and the skeletal consequences of the dysregulation of the serotonergic system in both human and animal studies. [ABSTRACT FROM AUTHOR]

Tumor recurrence is a paradoxical function of a machinery, whereby a small proportion of the cancer cell population enters a resistant, dormant state, persists long-term in this condition, and then transitions to proliferation. The dormant phenotype is typical of cancer stem cells, tumor-initiating cells, disseminated tumor cells, and drug-tolerant persisters, which all demonstrate similar or even equivalent properties. Cancer cell dormancy and its conversion to repopulation are regulated by several protein signaling systems that inhibit or induce cell proliferation and provide optimal interrelations between cancer cells and their special niche; these systems act in close connection with tumor microenvironment and immune response mechanisms. During dormancy and reawakening periods, cell proteostasis machineries, autophagy, molecular chaperones, and the unfolded protein response are recruited to protect refractory tumor cells from a wide variety of stressors and therapeutic insults. Proteostasis mechanisms functionally or even physically interfere with the main regulators of tumor relapse, and the significance of these interactions and implications in the tumor recurrence phases are discussed in this review. [ABSTRACT FROM AUTHOR]

High‐risk neuroblastoma patients have poor survival rates and require better therapeutic options. High expression of a multifunctional DNA and RNA‐binding protein, NONO, in neuroblastoma is associated with poor patient outcome; however, there is little understanding of the mechanism of NONO‐dependent oncogenic gene regulatory activity in neuroblastoma. Here, we used cell imaging, biochemical and genome‐wide molecular analysis to reveal complex NONO‐dependent regulation of gene expression. NONO forms RNA‐ and DNA‐tethered condensates throughout the nucleus and undergoes phase separation in vitro, modulated by nucleic acid binding. CLIP analyses show that NONO mainly binds to the 5′ end of pre‐mRNAs and modulates pre‐mRNA processing, dependent on its RNA‐binding activity. NONO regulates super‐enhancer‐associated genes, including HAND2 and GATA2. Abrogating NONO RNA binding, or phase separation activity, results in decreased expression of HAND2 and GATA2. Thus, future development of agents that target RNA‐binding activity of NONO may have therapeutic potential in this cancer context. Synopsis: NONO protein correlates with poor outcome in neuroblastoma. NONO binds 5′ ends of introns in oncogenic genes, including super‐enhancer‐regulated GATA2 and HAND2, enabling proper RNA processing, via RNA binding and phase separation activities. In neuroblastoma, the multifunctional protein NONO binds to the 5′ intronic regions of pre‐mRNA in non‐paraspeckle nuclear puncta.Some NONO puncta correspond to transcription sites for super‐enhancer regulated GATA2 and HAND2 genes, where NONO enhances RNA processing at the 5′ end, leading to robust gene expression.NONO RNA binding and low‐complexity domains are required for its activity that is also diminished by BRD4 inhibitors, suggesting the puncta are phase separated condensates. [ABSTRACT FROM AUTHOR]

Cells activate protective mechanisms to overcome stressful conditions that threaten cellular homeostasis, including imbalances in calcium, redox, and nutrient levels. Endoplasmic reticulum (ER) stress activates an intracellular signaling pathway, known as the unfolded protein response (UPR), to mitigate such circumstances and protect cells. Although ER stress is sometimes a negative regulator of autophagy, UPR induced by ER stress typically activates autophagy, a self-degradative pathway that further supports its cytoprotective role. Sustained activation of ER stress and autophagy is known to trigger cell death and is considered a therapeutic target for certain diseases. However, ER stress-induced autophagy can also lead to treatment resistance in cancer and exacerbation of certain diseases. Since the ER stress response and autophagy affect each other, and the degree of their activation is closely related to various diseases, understanding their relationship is very important. In this review, we summarize the current understanding of two fundamental cellular stress responses, the ER stress response and autophagy, and their crosstalk under pathological conditions to help develop therapies for inflammatory diseases, neurodegenerative disorders, and cancer. [ABSTRACT FROM AUTHOR]

Gain-of-function mutations of SHP2, especially D61Y and E76K, lead to the development of neoplasms in hematopoietic cells. Previously, we found that SHP2-D61Y and -E76K confer HCD-57 cells cytokine-independent survival and proliferation via activation of MAPK pathway. Metabolic reprogramming is likely to be involved in leukemogenesis led by mutant SHP2. However, detailed pathways or key genes of altered metabolisms are unknown in leukemia cells expressing mutant SHP2. In this study, we performed transcriptome analysis to identify dysregulated metabolic pathways and key genes using HCD-57 transformed by mutant SHP2. A total of 2443 and 2273 significant differentially expressed genes (DEGs) were identified in HCD-57 expressing SHP2-D61Y and -E76K compared with parental cells as the control, respectively. Gene ontology (GO) and Reactome enrichment analysis showed that a large proportion of DEGs were involved in the metabolism process. Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis showed that DEGs were the mostly enriched in glutathione metabolism and biosynthesis of amino acids in metabolic pathways. Gene Set Enrichment Analysis (GSEA) revealed that the expression of mutant SHP2 led to a significant activation of biosynthesis of amino acids pathway in HCD-57 expressing mutant SHP2 compared with the control. Particularly, we found that ASNS, PHGDH, PSAT1, and SHMT2 involved in the biosynthesis of asparagine, serine, and glycine were remarkably up-regulated. Together, these transcriptome profiling data provided new insights into the metabolic mechanisms underlying mutant SHP2-driven leukemogenesis. [ABSTRACT FROM AUTHOR]

Circadian rhythms are natural rhythms that widely exist in all creatures, and regulate the processes and physiological functions of various biochemical reactions. The circadian clock is critical for cancer occurrence and progression. Its function is regulated by metabolic activities, and the expression and transcription of various genes. This review summarizes the composition of the circadian clock; the biological basis for its function; its relationship with, and mechanisms in, cancer; its various functions in different cancers; the effects of anti-tumor treatment; and potential therapeutic targets. Research in this area is expected to advance understanding of circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1) in tumor diseases, and contribute to the development of new anti-tumor treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB) is the most common extracranial solid tumor occurring during childhood and high-risk NB patients have a poor prognosis. The amplified MYCN gene serves as an important determinant of a high risk of NB. Methods: We performed an integrative screen using public NB tissue and cell line data, and identified that SMAD9 played an important role in high-risk NB. An investigation of the super-enhancers database (SEdb) and chromatin immunoprecipitation sequencing (ChIP-seq) dataset along with biological experiments of incorporating gene knockdown and CRISPR interference (CRISPRi) were performed to identify upstream regulatory mechanism of SMAD9. Gene knockdown and rescue, quantitative real-time PCR (Q-RT-PCR), cell titer Glo assays, colony formation assays, a subcutaneous xenograft model and immunohistochemistry were used to determine the functional role of SMAD9 in NB. An integrative analysis of ChIP-seq data with the validation of CRISPRi and dual-luciferase reporter assays and RNA sequencing (RNA-seq) data with Q-RT-PCR validation was conducted to analyze the downstream regulatory mechanism of SMAD9. Results: High expression of SMAD9 was specifically induced by the transcription factors including MYCN, PHOX2B, GATA3 and HAND2 at the enhancer region. Genetic suppression of SMAD9 inhibited MYCN-amplified NB cell proliferation and tumorigenicity both in vitro and in vivo. Further studies revealed that SMAD9 bound to the MYCN promoter and transcriptionally regulate MYCN expression, with MYCN reciprocally binding to the SMAD9 enhancer and transactivating SMAD9, thus forming a positive feedback loop along with the MYCN-associated cancer cell cycle. Conclusion: This study delineates that SMAD9 forms a positive transcriptional feedback loop with MYCN and represents a unique tumor-dependency for MYCN-amplified neuroblastoma. [ABSTRACT FROM AUTHOR]

The impact of asparaginases on plasma asparagine and glutamine is well established. However, the effect of asparaginases, particularly those derived from Erwinia chrysanthemi (also called crisantaspase), on circulating levels of other amino acids is unknown. We examined comprehensive plasma amino acid panel measurements in healthy immunodeficient/immunocompetent mice as well as in preclinical mouse models of acute myeloid leukemia (AML) and pancreatic ductal adenocarcinoma (PDAC) using long-acting crisantaspase, and in an AML clinical study (NCT02283190) using shortacting crisantaspase. In addition to the expected decrease of plasma glutamine and asparagine, we observed a significant increase in plasma serine and glycine post-crisantaspase. In PDAC tumors, crisantaspase treatment significantly increased expression of serine biosynthesis enzymes. We then systematically reviewed clinical studies using asparaginase products to determine the extent of plasma amino acid reporting and found that only plasma levels of glutamine/glutamate and asparagine/aspartate were reported, without measuring other amino acid changes post-asparaginase. To the best of our knowledge, we are the first to report comprehensive plasma amino acid changes in mice and humans treated with asparaginase. As dysregulated serine metabolism has been implicated in tumor development, our findings offer insights into how leukemia/cancer cells may potentially overcome glutamine/asparagine restriction, which can be used to design future synergistic therapeutic approaches. [ABSTRACT FROM AUTHOR]

Ki‐67 is a chromatin‐associated protein with a dynamic distribution pattern throughout the cell cycle and is thought to be involved in chromatin organization. The lack of genomic interaction maps has hampered a detailed understanding of its roles, particularly during interphase. By pA‐DamID mapping in human cell lines, we find that Ki‐67 associates with large genomic domains that overlap mostly with late‐replicating regions. Early in interphase, when Ki‐67 is present in pre‐nucleolar bodies, it interacts with these domains on all chromosomes. However, later in interphase, when Ki‐67 is confined to nucleoli, it shows a striking shift toward small chromosomes. Nucleolar perturbations indicate that these cell cycle dynamics correspond to nucleolar maturation during interphase, and suggest that nucleolar sequestration of Ki‐67 limits its interactions with larger chromosomes. Furthermore, we demonstrate that Ki‐67 does not detectably control chromatin‐chromatin interactions during interphase, but it competes with the nuclear lamina for interaction with late‐replicating DNA, and it controls replication timing of (peri)centromeric regions. Together, these results reveal a highly dynamic choreography of genome interactions and roles for Ki‐67 in heterochromatin organization. Synopsis: pA‐DamID mapping and perturbation experiments reveal that Ki‐67 interacts in interphase with late‐replicating genomic regions in pre‐nucleolar bodies and in nucleoli, in competition with the nuclear lamina. The results uncover roles for Ki‐67 in nuclear organisation and control of replication timing. pA‐DamID maps reveal genome‐wide interaction patterns of Ki‐67 in interphase.Ki‐67 interacts with late‐replicating genomic regions in pre‐nucleolar bodies and in nucleoli.Ki‐67 controls replication timing of centromeric regions. [ABSTRACT FROM AUTHOR]

Abnormal CDK4/6-Rb-E2F signal transduction is a common finding in tumors and is a driving factor for the excessive proliferation of various tumor cells. PD-0332991, a highly specific, small molecule inhibitor for CDK4 and 6, has been shown to inhibit tumor growth by abrogating the phosphorylating capacity of CDK4/6 and suppressing Rb phosphorylation. It has been promoted for the treatment of breast cancer and potentially for other tumor types such as liver cancers, lung cancers and sarcomas. Due to the risk of monotherapy resistance, PD-0332991 is commonly used in combination with other drugs. Such combination treatments have proved able to inhibit tumor proliferation more effectively, induce stronger senescence and apoptosis, and enhance the efficiency of immunotherapy. Therefore, tumor cells with senescence induced by PD-0332991 are now used as ideal screening tools of cytolytic drugs with more efficient and thorough anti-tumor properties. With more extensive understandings about the branching points between senescence and apoptosis, it is possible to refine the dosage of PD-0332991. Better characterization of resistant cells, of inhibitors and of adverse effects such as leukopenia are needed to overcome obstacles in the use of PD-0332991. In this review of PD-0332991 research, we hope to provide guidance of transitions from laboratory findings to clinical applications of PD-0332991 and to facilitate PD-0332991-based multi-inhibitor combination therapies for various tumors. [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinases (CDKs) 4/6 inhibitors are a type of cell cycle regulation that prevents cell proliferation by blocking retinoblastoma protein (Rb) phosphorylation in the G1 to S phase transition. CDK 4/6 inhibitors are currently used mainly in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer in combination with endocrine therapy. However, primary or acquired resistance to drugs severely affect drug efficacy. Our study aims at summarizing and visualizing the current research direction and development trend of CDK4/6 inhibitor resistance to provide clinicians and research power with a summary of the past and ideas for the future. Methods: The Web of Science Core Collection and PubMed was searched for all included articles on CDK4/6 inhibitor resistance for bibliometric statistics and graph plotting. The metrological software and graphing tools used were R language version 4.2.0, Bibliometrix 4.0.0, Vosviewer 1.6.18, GraphPad Prism 9, and Microsoft Excel 2019. Results: A total of 1278 English-language articles related to CDK4/6 inhibitor resistance were included in the Web of Science core dataset from 1996-2022, with an annual growth rate of14.56%. In PubMed, a total of 1123 articleswere counted in the statistics, with an annual growth rate of 17.41% Cancer Research is the most included journal (102/1278, 7.98%) with an impact factor of 13.312 and is theQ1 of the Oncology category of the Journal Citation Reports. Professor Malorni Luca from Italy is probably themost contributing author in the current field (Publications 21/1278, 1.64%), while Prof. Turner Nicholas C from the USA is perhaps the most authoritative new author in the field of CDK4/6 inhibitor resistance (Total Citations2584, M-index 1.429). The main research efforts in this field are currently focused on Palbociclib and Abemaciclib. Studies on drug resistance mechanisms or post-drug resistance therapies focus onMEK inhibitors and related pathways, PI3K-AKT-MTOR pathways or inhibitors, EGFR-related pathways, EGFR inhibitors, TKI inhibitors, MAPK pathways and inhibitors, and so on. Conclusion: This study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and mining research neglect directions. [ABSTRACT FROM AUTHOR]

Neuroblastoma poses significant challenges in clinical management. Despite its relatively low incidence, this malignancy contributes disproportionately to cancer-related childhood mortality. Tailoring treatments based on risk stratification, including MYCN oncogene amplification, remains crucial, yet high-risk cases often confront therapeutic resistance and relapse. Here, we explore the aryl hydrocarbon receptor (AHR), a versatile transcription factor implicated in diverse physiological functions such as xenobiotic response, immune modulation, and cell growth. Despite its varying roles in malignancies, AHR's involvement in neuroblastoma remains elusive. Our study investigates the interplay between AHR and its ligand kynurenine (Kyn) in neuroblastoma cells. Kyn is generated from tryptophan (Trp) by the activity of the enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2). We found that neuroblastoma cells displayed sensitivity to the TDO2 inhibitor 680C91, exposing potential vulnerabilities. Furthermore, combining TDO2 inhibition with retinoic acid or irinotecan (two chemotherapeutic agents used to treat neuroblastoma patients) revealed synergistic effects in select cell lines. Importantly, clinical correlation analysis using patient data established a link between elevated expression of Kyn-AHR pathway genes and adverse prognosis, particularly in older children. These findings underscore the significance of the Kyn-AHR pathway in neuroblastoma progression, emphasizing its potential role as a therapeutic target., (© 2024 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

HCC is the most frequent primary liver cancer with an extremely poor prognosis and often develops on preset of chronic liver diseases. Major risk factors for HCC include metabolic dysfunction-associated steatohepatitis, a complex multifactorial condition associated with abnormal endoplasmic reticulum (ER) proteostasis. To cope with ER stress, the unfolded protein response engages adaptive reactions to restore the secretory capacity of the cell. Recent advances revealed that ER stress signaling plays a critical role in HCC progression. Here, we propose that chronic ER stress is a common transversal factor contributing to the transition from liver disease (risk factor) to HCC. Interventional strategies to target the unfolded protein response in HCC, such as cancer therapy, are also discussed., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Autophagy, as a highly conserved cellular process, participates in cellular homeostasis by degradation and recycling of damaged organelles and proteins. Besides, autophagy has been evidenced to play a dual role through cancer initiation and progression. In the early stage, it may have a tumor-suppressive function through inducing apoptosis and removing damaged cells and organelles. However, late stages promote tumor progression by maintaining stemness features and induction of chemoresistance. Therefore, identifying and targeting molecular mechanisms involved in autophagy is a potential therapeutic strategy for human cancers. Multiple transcription factors (TFs) are involved in the regulation of autophagy by modulating the expression of autophagy-related genes (ATGs). In addition, a wide array of long noncoding RNAs (lncRNAs), a group of regulatory ncRNAs, have been evidenced to regulate the function of these autophagy-related TFs through tumorigenesis. Subsequently, the lncRNAs/TFs/ATGs axis shows great potential as a therapeutic target for human cancers. Therefore, this review aimed to summarize new findings about the role of lncRNAs in regulating autophagy-related TFs with therapeutic perspectives., (© 2024 John Wiley & Sons Ltd.)

Autophagy is a catabolic process that captures cellular waste and degrades them in the lysosome. The main functions of autophagy are quality control of cytosolic proteins and organelles, and intracellular recycling of nutrients in order to maintain cellular homeostasis. Autophagy is upregulated in many cancers to promote cell survival, proliferation, and metastasis. Both cell‐autonomous autophagy (also known as tumor autophagy) and non‐cell‐autonomous autophagy (also known as host autophagy) support tumorigenesis through different mechanisms, including inhibition of p53 activation, sustaining redox homeostasis, maintenance of essential amino acids levels in order to support energy production and biosynthesis, and inhibition of antitumor immune responses. Therefore, autophagy may serve as a tumor‐specific vulnerability and targeting autophagy could be a novel strategy in cancer treatment. [ABSTRACT FROM AUTHOR]

While numerous targeted therapies have been recently adopted to improve the treatment of hematologic malignancies, acquired or intrinsic resistance poses a significant obstacle to their efficacy. Thus, there is increasing need to identify novel, targetable pathways to further improve therapy for these diseases. The integrated stress response is a signaling pathway activated in cancer cells in response to both dysregulated growth and metabolism, and also following exposure to many therapies that appears one such targetable pathway for improved treatment of these diseases. In this review, we discuss the role of the integrated stress response in the biology of hematologic malignancies, its critical involvement in the mechanism of action of targeted therapies, and as a target for pharmacologic modulation as a novel strategy for the treatment of hematologic malignancies. [ABSTRACT FROM AUTHOR]

Diseases and environmental stresses are two distinct challenges for virtually all living organisms. In light of evolution, cellular responses to diseases and stresses might share similar molecular mechanisms, but the detailed regulation pathway is not reported yet. We obtained the transcriptomes and translatomes from several NSCLC (non-small-cell lung cancer) patients as well as from different species under normal or stress conditions. We found that the translation level of gene ATF4 is remarkably enhanced in NSCLC due to the reduced number of ribosomes binding to its upstream open reading frames (uORFs). We also showed the evolutionary conservation of this uORF-ATF4 regulation in the stress response of other species. Molecular experiments showed that knockdown of ATF4 reduced the cell growth rate while overexpression of ATF4 enhanced cell growth, especially for the ATF4 allele with mutated uORFs. Population genetics analyses in multiple species verified that the mutations that abolish uATGs (start codon of uORFs) are highly deleterious, suggesting the functional importance of uORFs. Our study proposes an evolutionarily conserved pattern that enhances the ATF4 translation by uORFs upon stress or disease. We generalized the concept of cellular response to diseases and stresses. These two biological processes may share similar molecular mechanisms. [ABSTRACT FROM AUTHOR]

Background: The majority of high-risk neuroblastomas harbor telomerase activity, and telomerase-interacting compounds, such as 6-thio-2'-deoxyguanosine (6-thio-dG), have been found to impair the growth of telomerase-positive neuroblastoma cell lines. It has remained unclear, however, how such drugs can be combined with other compounds used in current treatment concepts for neuroblastoma patients. Methods: Growth-inhibitory effects of varying concentrations of 6-thio-dG in combination with etoposide, doxorubicin or ceritinib were determined in eight telomerase-positive neuroblastoma cell lines with distinct genetic backgrounds. Tumor growth inhibition of subcutaneous xenografts from three different cell lines was assessed upon treatment with 6-thio-dG, the competitive telomerase inhibitor imetelstat, etoposide, or combinations of these compounds. Results: Robust synergistic anti-tumor effects were observed for combinations of 6-thio-dG and etoposide or doxorubicin, but not for 6-thio-dG and ceritinib, in telomerase-positive neuroblastoma cell lines in vitro. Treatment of mouse xenografts with combinations of 6-thio-dG and etoposide significantly attenuated tumor growth and improved mouse survival over etoposide alone in two of three cell line models. Treatment of xenograft tumors by imetelstat monotherapy decreased telomerase activity by roughly 50% and significantly improved survival over control in all three models, whereas treatment with imetelstat plus etoposide led to enhanced survival over etoposide monotherapy in one model. Mechanistically, the synergistic effect was found to be due to both increased apoptosis and cell cycle arrest. Conclusion: Our study indicates that telomerase is an actionable target in telomerase-positive neuroblastoma, and demonstrates that combination therapies including telomerase-interacting compounds may improve the efficacy of established cytotoxic drugs. Targeting telomerase may thus represent a therapeutic option in high-risk neuroblastoma patients. [ABSTRACT FROM AUTHOR]

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib's unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Protein acetylation is a reversible post-translational modification, and is involved in many biological processes in cells, such as transcriptional regulation, DNA damage repair, and energy metabolism, which is an important molecular event and is associated with a wide range of diseases such as cancers. Protein acetylation is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) in homeostasis. The abnormal acetylation level might lead to the occurrence and deterioration of a cancer, and is closely related to various pathophysiological characteristics of a cancer, such as malignant phenotypes, and promotes cancer cells to adapt to tumor microenvironment. Therapeutic modalities targeting protein acetylation are a potential therapeutic strategy. This article discussed the roles of protein acetylation in tumor pathology and therapeutic drugs targeting protein acetylation, which offers the contributions of protein acetylation in clarification of carcinogenesis, and discovery of therapeutic drugs for cancers, and lays the foundation for precision medicine in oncology. [ABSTRACT FROM AUTHOR]

Platinum-based chemotherapies such as cisplatin are used as first-line treatment for the paediatric tumour neuroblastoma. Although the majority of neuroblastoma tumours respond to therapy, there is a high fraction of high-risk neuroblastoma patients that eventually relapse with increased resistance. Here, we show that one key determinant of cisplatin sensitivity is phosphorylation of the cyclin-dependent kinase inhibitor p21Cip1/Waf1. A panel of eight neuroblastoma cell lines and a TH-MYCN mouse model were investigated for the expression of p21Cip1/Waf1 using RT-qPCR, Western blot, and immunofluorescence. This was followed by investigation of sensitivity towards cisplatin and the p21Cip1/Waf1 inhibitor UC2288. Whereas the cell lines and the mouse model showed low levels of un-phosphorylated p21Cip1/Waf1, the phosphorylated p21Cip1/Waf1 (Thr145) was highly expressed, which in the cell lines correlated to cisplatin resistance. Furthermore, the neuroblastoma cell lines showed high sensitivity to UC2288, and combination treatment with cisplatin resulted in considerably decreased cell viability and delay in regrowth in the two most resistant cell lines, SK-N-DZ and BE(2)-C. Thus, targeting p21Cip1/Waf1 can offer new treatment strategies and subsequently lead to the design of more efficient combination treatments for high-risk neuroblastoma. [ABSTRACT FROM AUTHOR]

Introduction: Insulin-like growth factor type 1 receptor (IGF1R) is overexpressed in various malignant tumors, which relates to their transformation and recurrence. Craniopharyngioma is a benign tumor with malignant results, often accompanied by a severe inflammatory reaction. However, the relationship between IGF1R expression and the inflammatory response of craniopharyngioma is unclear. Methods: We enrolled 85 patients with adamantinomatous craniopharyngioma (ACP) in a study to explore the relationship between IGF1R expression and clinical features of this disease. Results: Patients in the IGF1R high-expression group had a significantly higher incidence of hypopituitarism, higher recurrence rate, and lower progression-free survival. β-Catenin can further regulate expression of the stem cell marker, CD44, by regulating IGF1R. Using immunofluorescence, we found that tumor stem cell-like cells did not express phosphorylated (p)-ERK, although p-ERK activation was evident in the surrounding cells. Picropodophyllin, a specific inhibitor of IGF1R, increased the expression of p-ERK protein and decreased the transcription level of interleukin-6. Conclusions: High expression of IGF1R might promote inflammation of ACP, which might be an unfavorable factor for pituitary function and prognosis. The high expression of IGF1R in tumor stem cell-like cells might inhibit the expression of p-ERK and promote the generation of inflammatory factors. IGF1R plays a stemness maintenance role in ACP and regulates the production of inflammatory factors through a p-ERK pathway, which suggests that targeting IGF1R and p-ERK might provide a new direction for alleviating tumor inflammation. [ABSTRACT FROM AUTHOR]

Globally, breast cancer is the most common malignancy in women. Substantial efforts have been made to develop novel therapies, including targeted therapies and immunotherapies, for patients with breast cancer who do not respond to standard therapies. Consequently, new targeted therapies, such as cyclin-dependent kinase 4 and 6 inhibitors, poly (ADP-ribose) polymerase inhibitors, phosphoinositide 3-kinase inhibitor, and antibody–drug conjugates targeting human epidermal growth factor receptor 2 or trophoblast cell surface antigen-2, and immune checkpoint inhibitor targeting programmed cell death-1, have been developed and are now in clinical use. However, only some patients have benefited from these novel therapies; therefore, the identification and validation of reliable or more accurate biomarkers for predicting responses to these agents remain a major challenge. This review summarizes the currently available predictive biomarkers for breast cancer and describes recent efforts undertaken to identify potential predictive markers for molecularly targeted therapies and immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

The ALK gene encodes a tyrosine kinase receptor characterized by an expression pattern mainly restricted to the developing central and peripheral nervous systems. In 2008, the discovery of ALK activating mutations in neuroblastoma, a tumor of the sympathetic nervous system, represented a breakthrough in the understanding of the pathogenesis of this pediatric cancer and established mutated ALK as a tractable therapeutic target for precision medicine. Subsequent studies addressed the identity of ALK ligands, as well as its physiological function in the sympathoadrenal lineage, its role in neuroblastoma development and the signaling pathways triggered by mutated ALK. This review focuses on these different aspects of the ALK biology and summarizes the various therapeutic strategies relying on ALK inhibition in neuroblastoma, either as monotherapies or combinatory treatments.

Background: Neuroblastoma (NB), a childhood tumor derived from the sympathetic nervous system, presents with heterogeneous clinical behavior. While some tumors regress spontaneously without medical intervention, others are resistant to therapy, associated with an aggressive phenotype. MYCN-amplification, frequently occurring in high-risk NB, is correlated with an undifferentiated phenotype and poor prognosis. Differentiation induction has been proposed as a therapeutic approach for high-risk NB. We have previously shown that MYCN maintains an undifferentiated state via regulation of the miR-17 ~ 92 microRNA cluster, repressing the nuclear hormone receptors (NHRs) estrogen receptor alpha (ERα) and the glucocorticoid receptor (GR). Methods: Cell viability was determined by WST-1. Expression of differentiation markers was analyzed by Western blot, RT-qPCR, and immunofluorescence analysis. Metabolic phenotypes were studied using Agilent Extracellular Flux Analyzer, and accumulation of lipid droplets by Nile Red staining. Expression of angiogenesis, proliferation, and neuronal differentiation markers, and tumor sections were assessed by immunohistochemistry. Gene expression from NB patient as well as adrenal gland cohorts were analyzed using GraphPad Prism software (v.8) and GSEA (v4.0.3), while pseudo-time progression on post-natal adrenal gland cells from single-nuclei transcriptome data was computed using scVelo. Results: Here, we show that simultaneous activation of GR and ERα potentiated induction of neuronal differentiation, reduced NB cell viability in vitro, and decreased tumor burden in vivo. This was accompanied by a metabolic reprogramming manifested by changes in the glycolytic and mitochondrial functions and in lipid droplet accumulation. Activation of the retinoic acid receptor alpha (RARα) with all-trans retinoic acid (ATRA) further enhanced the differentiated phenotype as well as the metabolic switch. Single-cell nuclei transcriptome analysis of human adrenal glands indicated a sequential expression of ERα, GR, and RARα during development from progenitor to differentiated chromaffin cells. Further, in silico analysis revealed that patients with higher combined expression of GR, ERα, and RARα mRNA levels had elevated expression of neuronal differentiation markers and a favorable outcome. Conclusion: Together, our findings suggest that combination therapy involving activation of several NHRs could be a promising pharmacological approach for differentiation treatment of NB patients. [ABSTRACT FROM AUTHOR]

The unfolded protein response (UPR) is an adaptive stress response pathway that is essential for cancer cell survival under endoplasmic reticulum stress such as during glucose starvation. In this study, we identified spautin-1, an autophagy inhibitor that suppresses ubiquitin-specific peptidase 10 (USP10) and USP13, as a novel UPR inhibitor under glucose starvation conditions. Spautin-1 prevented the induction of UPR-associated proteins, including glucose-regulated protein 78, activating transcription factor 4, and a splicing variant of x-box-binding protein-1, and showed preferential cytotoxicity in glucose-starved cancer cells. However, USP10 and USP13 silencing and treatment with other autophagy inhibitors failed to result in UPR inhibition and preferential cytotoxicity during glucose starvation. Using transcriptome and chemosensitivity-based COMPARE analyses, we identified a similarity between spautin-1 and mitochondrial complex I inhibitors and found that spautin-1 suppressed the activity of complex I extracted from isolated mitochondria. Our results indicated that spautin-1 may represent an attractive mitochondria-targeted seed compound that inhibits the UPR and cancer cell survival during glucose starvation. [ABSTRACT FROM AUTHOR]