Molecular Cancer Research最新文献

{"title":"VAV2 Drives EGFR-Mediated Rac1 Responses in Prostate Cancer.","authors":"Martin J Baker, Suli Zhang, Daniel Zhang, Joshua Searle, Priti Lal, Cornelis P Vlaar, Surangani Dharmawardhane, Martín C Abba, Marcelo G Kazanietz, Mariana Cooke","doi":"10.1158/1541-7786.MCR-24-0957","DOIUrl":"10.1158/1541-7786.MCR-24-0957","url":null,"abstract":"<p><p>The small G-protein Rac1 is a central player in cancer progression and metastatic dissemination. Rac1 has been established as a bona fide effector of receptor tyrosine kinases, acting as a signaling node for motility, invasiveness, mitogenesis, and gene expression. Previous studies demonstrated that Rac1 is hyperactivated in aggressive cellular models of prostate cancer. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of Rac1 results in impaired proliferation and migration of prostate cancer cells. Rac1-null cells display profound alterations in transcriptional programs, particularly those associated with cell adhesion and extracellular matrix regulation. Combined expression profiling and unbiased RNAi screening of Rac1 guanine nucleotide exchange factors identified VAV2 as the foremost mediator EGF-induced GTP loading onto Rac1 in prostate cancer cells. Depletion of VAV2 from prostate cancer cells significantly reduced their proliferative and migratory capacities without affecting the expression of Rac1-regulated genes, suggesting that VAV2 controls a discrete subset of Rac1-dependent cellular responses. IHC assessment in human prostate biopsies showed significant VAV2 overexpression in tumor areas. Bioinformatic analysis revealed a strong correlation between VAV2 expression and poor clinical prognosis. In addition to uncovering a prominent role for VAV2-Rac1 as an effector pathway mediating EGFR-driven proliferative and migratory responses in prostate cancer cells, our findings underscore the potential prognostic value of VAV2 in human prostate cancer progression.</p><p><strong>Implications: </strong>This study highlights the central role of VAV2 in prostate cancer cell proliferation and migration, as well as its potential prognostic value in disease progression.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"684-698"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Cancer Therapy on the Cells and Extracellular Vesicles of the Tumor Immune Microenvironment.","authors":"Claire Bruno, Andrew Whitcomb, Brooke Pincock, Israel Davila Aleman, Jacob H Neves, Matthew Shaw, Amber Gonda","doi":"10.1158/1541-7786.MCR-25-0101","DOIUrl":"10.1158/1541-7786.MCR-25-0101","url":null,"abstract":"<p><p>Cancer remains one of the leading causes of morbidity and mortality worldwide, necessitating the development of diverse treatment options to improve patient outcomes. The tumor microenvironment (TME) plays a critical role in determining the efficacy of these different therapies, yet the reciprocal impact of treatment on the TME, particularly the tumor immune microenvironment (TIME), remains incompletely understood. This review investigates the different effects of cancer therapies-chemotherapy, targeted therapy, immunotherapy, and radiotherapy-on immune cells within the TIME and associated extracellular vesicles (EV). The broader impact on the TME belies a complex and nuanced tumor response. These treatments have been shown to have an impact on the function of various immune cells, influencing their activity to either promote or block tumor growth. Importantly, this review also considers how these therapies play an indirect role in modulating the TIME by influencing the release and contents of EVs, highlighting the significant role that EVs play in intercellular communication within the TIME. By analyzing recent findings, this review aims to provide a comprehensive understanding of how different cancer therapies reshape the TIME. Understanding these dynamic relationships can help pave the way for optimizing existing treatments, developing new therapies, and enhancing patient outcomes.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"673-683"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial Analysis of Hereditary Diffuse Gastric Cancer Reveals Indolent Phenotype of Signet Ring Cell Precursors.","authors":"Amber F Gallanis, Lauren A Gamble, Cihan Oguz, Sarah G Samaranayake, Noemi Kedei, Maria O Hernandez, Madeline Wong, Desiree Tillo, Benjamin L Green, Paul McClelland, Cassidy Bowden, Irene Gullo, Mark Raffeld, Liqiang Xi, Michael Kelly, Markku Miettinen, Martha Quezado, Sun A Kim, Andrew M Blakely, Justin Lack, Theo Heller, Jonathan M Hernandez, Jeremy L Davis","doi":"10.1158/1541-7786.MCR-24-1039","DOIUrl":"10.1158/1541-7786.MCR-24-1039","url":null,"abstract":"<p><p>Germline CDH1 loss-of-function mutations are causally linked to an increased lifetime risk of diffuse gastric cancer (DGC). Early, multifocal signet ring cell (SRC) lesions are ubiquitous among CDH1 variant carriers, yet only a subset of patients will develop advanced DGC. A multiomic analysis was performed to establish the molecular phenotype of early SRC lesions and how they differ from advanced DGC using 20 samples from human total gastrectomy specimens of germline CDH1 variant carriers. Spatial transcriptomic analysis demonstrated reduced CDH1 gene expression and increased expression of extracellular matrix remodeling in SRC lesions compared with unaffected adjacent gastric epithelium. Single-cell RNA sequencing revealed an SRC-enriched signature with markers REG1A, VIM, AQP5, PRR4, MUC6, and AGR2. Importantly, SRC lesions lacked alterations in known drivers of gastric cancer (TP53, ARID1A, and KRAS) and activation of associated signal transduction pathways. Advanced DGC demonstrated E-cadherin reexpression, somatic TP53 and ERBB3 mutations, and upregulated CTNNA1, MYC, and MET expression when compared with SRC lesions.</p><p><strong>Implications: </strong>The marked differences in the genomic and transcriptomic profiles of SRC lesions and advanced DGC support the consideration of SRC lesions as precancers in patients with germline CDH1 mutations.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"699-709"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3 Promotes Gastric Cancer Progression via Modulation of FNTA-Mediated KRAS/ERK Signaling Activation.","authors":"Fangqi Hu, Song Zhang, Jie Chai","doi":"10.1158/1541-7786.MCR-24-1168","DOIUrl":"10.1158/1541-7786.MCR-24-1168","url":null,"abstract":"<p><p>As a vital form of posttranscriptional modification, RNA N6-methyladenosine (m6A) methylation dysregulation is usually associated with the pathogenesis of a range of diseases, including cancer, but the function and underlying mechanisms of m6A in regulating gastric cancer initiation and progression are still poorly understood. In this study, we have found that methyltransferase-like 3 (METTL3) and the level of RNA m6A modification were significantly upregulated in gastric cancerous tissues relative to their normal counterparts. In addition, higher METTL3 expression always predicted poorer outcomes for patients with gastric cancer. Methylated RNA sequencing revealed that METTL3 deposited m6A modification on farnesyltransferase, subunit alpha (FNTA) mRNA and accelerated its translation relying on YTH N6-methyladenosine RNA-binding protein 1 recognition. When METTL3 or FNTA expression was silenced in gastric cancer cells, the FNTA-mediated KRAS plasma membrane distribution was disrupted, resulting in downstream MEK/ERK signaling inactivation, which finally contributed to gastric cancer suppression in vitro and in vivo. In summary, our studies revealed a cross-talk between METTL3-mediated RNA methylation and FNTA-mediated protein modification, which synergized to drive gastric cancer progression through orchestrating KRAS/ERK signaling activity.</p><p><strong>Implications: </strong>Targeting the METTL3/FNTA pathway will provide an alternative to overcome the resistance of gastric cancer to canonical KRAS inhibitors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"724-738"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The LINC00519/hsa-miR-22-3p/MECOM Axis Accelerates Intrahepatic Cholangiocarcinoma Progression Through PI3K/AKT Signaling.","authors":"Zhuxin Gu, Yanjun Sun, Fajing Chen, Weiwei Gu, Xiaohua Lu, Suming Zhao, Qinan Geng, Yang Yang","doi":"10.1158/1541-7786.MCR-25-0207","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0207","url":null,"abstract":"<p><p>Intrahepatic cholangiocarcinoma (ICC) is the second most common liver cancer. LINC00519 plays prominent roles in the progression of numerous cancers. To explore the molecular mechanism of LINC00519 in ICC, LINC00519, hsa-miR-22-3p, and MECOM expressions in ICC were assessed with ENCORI database and quantitative real-time PCR. Biological functions of LINC00519 in ICC were examined using clone formation experiment, Transwell analysis, flow cytometry, and Western blot. Meanwhile, the LINC00519 mechanism in ICC was determined by dual-luciferase reporter assay. Results showed that LINC00519 and MECOM were highly expressed in ICC, but hsa-miR-22-3p was decreased. Functionally, silencing LINC00519 weakened ICC cell proliferation, migration and induced cell apoptosis. Also, LINC00519 knockdown repressed PI3K/AKT pathway. Mechanistically, LINC00519 acted as a competitive endogenous RNA to target MECOM by sponging hsa-miR-22-3p. Meanwhile, rescue assays further proved that low LINC00519 expression restrained ICC cell proliferation and migration, and accelerated apoptosis through PI3K/AKT pathway by miR-22-3p/MECOM. In conclusion, this research revealed a novel LINC00519/hsa-miR-22-3p/MECOM regulatory axis and PI3K/AKT pathway that modulated ICC progression. Implications: This study deepens the understanding of the non-coding RNA regulatory network in ICC and provides potential targets for the diagnosis and targeted therapy of ICC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-catenin-cohesin ring-CEGRs/ALCDs axis activation contributes to the development of hepatoblastoma and fibrolamellar HCC.","authors":"Yasmeen Fleifil, Ruhi Gulati, Katherine Jennings, Ina Kycia, Alex Bondoc, Gregory Tiao, James Geller, Matthew Weirauch, Khashayar Vakili, Lubov Timchenko, Nikolai Timchenko","doi":"10.1158/1541-7786.MCR-25-0236","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0236","url":null,"abstract":"<p><p>The pediatric and adolescent liver cancers Hepatoblastoma (HBL) and Fibrolamellar hepatocellular carcinoma (FLC) are dangerous diseases requiring aggressive surgery, when feasible, and non-targeted toxic chemotherapy for a chance of cure, due to insufficient knowledge of underlying molecular mechanisms. We've previously reported the essential role of ph-S675-β-catenin in the reorganization of genomic structure in HBL and FLC by oncogenic activation via chromosomal regions called Cancer Enhancing Genomic Regions or Aggressive Liver Cancer Domains (CEGRs/ALCDs). In FLC, the fusion J-PKAc oncoprotein phosphorylates β-catenin at Ser675, triggering such CEGRs/ALCDs-mediated activation of oncogenes. In this paper, we found that all members of the cohesin ring - CTCF, Rad21, SMC1, SMC3 and STAG1 - and β-catenin-TCF4 are bound to CEGRs/ALCDs of oncogenes in HBL and FLC, as well as many other cancers, and that this binding increases transcription. Examination of a large cohort of HBL and FLC samples revealed that cohesin ring expression is dramatically elevated in the majority. The cohesin ring, as well as the ph-S675-β-catenin-TCF4-p300 complex, are detected on both the promoter and intron-located CEGRs/ALCDs of NRF2 and Thy1, correlating with increased transcription. This suggests that the cohesin ring creates the DNA-loop for oncogene activation. The inhibition of the cohesin ring by JQ1 reduces proliferation of HBL and FLC cells in culture, as well as cells expressing the FLC-specific DNAJB1-PKAc fusion oncogene. Implications: These studies provide evidence that J-PKAc-β-catenin and the cohesin ring cooperate in oncogenic activation for both HBL and FLC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic Signatures of Poor Prognosis in Merkel Cell Carcinoma: A Single-Institution Prospective Study.","authors":"Joshua D Smith, Apurva D Bhangale, Wenjin Gu, Collin Brummel, Elizabeth Gensterblum-Miller, Scott McLean, Paul W Harms, Kelly L Harms, Christopher K Bichakjian, Matthew E Spector, Ryan E Mills, J Chad Brenner","doi":"10.1158/1541-7786.MCR-24-1138","DOIUrl":"10.1158/1541-7786.MCR-24-1138","url":null,"abstract":"<p><p>Merkel cell carcinoma (MCC) is an aggressive disease with poor survival outcomes and increasing incidence. There is a clear and present need for enhanced understanding of cellular mechanisms of tumorigenesis, validation of robust genetic signatures predictive of aggressive disease, and novel informatics tools to simplify analysis of Merkel cell polyomavirus (MCPyV)-host genome interactions. Genomic DNA was harvested from 54 MCC tumors for exome sequencing and in-depth genetic profiling of a 226-gene panel. We further developed a robust informatics package (MCPyViewer) optimized for MCPyV integration site analysis with graphical output to simplify usability for end-users. Finally, we assessed the prognostic impact of specific genetic signatures on MCC-specific survival in our cohort. Our study included 54 patients (n = 44 MCPyV-positive), 11 (20.4 %) of which had died of MCC at last follow-up. Human genes altered at high frequency included LRP1B (n = 10, 18.5 %), FAT1 (n = 9, 16.7 %), KMT2D (n = 9, 16.7 %), and RB1 (n = 7, 13.0 %). In 36 of 44 (81.8 %) MCPyV-positive tumors, we identified viral integration into the human genome with a median of two events per tumor. In six tumors, MCPyV integrated into COSMIC Tier 1 or Tier 2 cancer-related human genes. Implications: A combined genomics score incorporating tumor mutational burden and copy number variation was strongly prognostic of MCC-specific survival controlling for lymph node metastases and tumor MCPyV status, thus, our study adds critical understanding to prognostic markers and tumorigenic mechanisms in MCC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12336863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential control of growth and identity by HNF4α isoforms in pancreatic ductal adenocarcinoma.","authors":"Pengshu Fang, Emily R Wilson, Sydney N Larsen, Walter A Orellana, Margaret A Hall, Chris Stubben, Acramul Haque Kabir, Kajsa Affolter, Richard A Moffitt, Xiaoyang Zhang, Eric L Snyder","doi":"10.1158/1541-7786.MCR-25-0175","DOIUrl":"10.1158/1541-7786.MCR-25-0175","url":null,"abstract":"<p><p>Although transcriptomic studies have stratified pancreatic ductal adenocarcinoma (PDAC) into clinically relevant subtypes, classical or basal-like, further research is needed to identify the transcriptional regulators of each subtype. Previous studies identified HNF4α as a key regulator of the classical subtype. Still, the distinct contributions of its isoforms (P1 and P2), which display dichotomous functions in normal development and gastrointestinal malignancies, remain unexplored. Here, we show that HNF4α-positive human PDAC tumors exhibit uniform expression of P2-isoforms but variable expression of P1 isoforms. To dissect the roles of each isoform in PDAC, we performed functional, transcriptomic, and epigenetic analysis after exogenous expression in HNF4α-negative models or CRISPRi-mediated knockdown of endogenous isoforms. We demonstrated that P1 isoforms are less compatible with growth and stronger transcriptional regulators than P2. Despite both isoforms sharing a common DNA-binding domain, P1 isoforms displayed stronger binding at HNF4α target genes, resulting in increased transcriptional activity. These findings provide a detailed characterization of HNF4α P1 and P2 isoforms and their distinct roles in PDAC biology. Implications: HNF4α isoforms exhibit heterogeneous expression in PDAC and have distinct effects on proliferation and gene expression, including markers of clinically relevant molecular subtypes.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ribosome Profiling Reveals Translational Reprogramming via mTOR Activation in Omacetaxine-Resistant Multiple Myeloma.","authors":"Zachary J Walker, Katherine F Vaeth, Amber Baldwin, Denis J Ohlstrom, Lauren T Reiman, Kady A Dennis, Kate Matlin, Beau M Idler, Brett M Stevens, Neelanjan Mukherjee, Daniel W Sherbenou","doi":"10.1158/1541-7786.MCR-24-0444","DOIUrl":"10.1158/1541-7786.MCR-24-0444","url":null,"abstract":"<p><p>Protein homeostasis is critical to the survival of multiple myeloma cells. Although this is targeted with proteasome inhibitors, mRNA translation inhibition has not entered trials. Recent work illustrates broad sensitivity of multiple myeloma cells to the translation inhibitor omacetaxine. We hypothesized that understanding how multiple myeloma becomes resistant will lead to the development of drug combinations to prevent or delay relapse. We generated omacetaxine resistance in H929 and MM1S multiple myeloma cell lines and compared them with parental lines. Resistant lines displayed decreased sensitivity to omacetaxine, with EC50 > 100 nmol/L, compared with parental sensitivity of 24 to 54 nmol/L. As omacetaxine inhibits protein synthesis, we performed both RNA sequencing and ribosome profiling to identify shared and unique regulatory strategies of resistance. Transcripts encoding translation factors and containing a terminal oligopyrimidine sequence in their 5' untranslated region were translationally upregulated in both resistant cell lines. The mTOR pathway promotes the translation of terminal oligopyrimidine motif-containing mRNAs. Indeed, mTOR inhibition with Torin 1 restored partial sensitivity to omacetaxine in both resistant cell lines. The combination was synergistic in omacetaxine-naïve multiple myeloma cell lines, and a combination effect was observed in vivo. Primary multiple myeloma cells from patient samples were also sensitive to the combination. These results provide a rational approach for omacetaxine-based combination therapy in patients with multiple myeloma, which have historically shown better responses to multiagent regimens.</p><p><strong>Implications: </strong>Through the use of ribosome profiling, our findings indicate mTOR inhibition as a novel combination therapy for partnering with the translation inhibitor omacetaxine in the treatment of multiple myeloma.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"611-621"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DR5 Disulfide Bonding Functions as a Sensor and Effector of Protein Folding Stress.","authors":"Mary E Law, Zaafir M Dulloo, Samantha R Eggleston, Gregory P Takacs, Grace M Alexandrow, Young Il Lee, Mengxiong Wang, Brian Hardy, Hanyu Su, Bianca Forsyth, Parag Das, Pran K Datta, Chi-Wu Chiang, Abhisheak Sharma, Siva Rama Raju Kanumuri, Olga A Guryanova, Jeffrey K Harrison, Boaz Tirosh, Ronald K Castellano, Brian K Law","doi":"10.1158/1541-7786.MCR-24-0756","DOIUrl":"10.1158/1541-7786.MCR-24-0756","url":null,"abstract":"<p><p>New agents are needed that selectively kill cancer cells without harming normal tissues. The TRAIL ligand and its receptors, DR5 and DR4, exhibit cancer-selective toxicity. TRAIL analogs or agonistic antibodies targeting these receptors are available but have not yet received FDA approval for cancer therapy. Small molecules for activating DR5 or DR4 independently of protein ligands may activate TRAIL receptors as a monotherapy or potentiate the efficacy of TRAIL analogs and agonistic antibodies. Previously described disulfide bond-disrupting agents activate DR5 by altering its disulfide bonding through inhibition of protein disulfide isomerases ERp44, AGR2, and PDIA1. Work presented in this article extends these findings by showing that disruption of single DR5 disulfide bonds causes high-level DR5 expression, disulfide-mediated clustering, and activation of caspase 8/caspase 3-mediated proapoptotic signaling. Recognition of the extracellular domain of DR5 by various antibodies is strongly influenced by the pattern of DR5 disulfide bonding, which has important implications for the use of agonistic DR5 antibodies for cancer therapy and as research tools. Importantly, other endoplasmic reticulum (ER) stressors, including thapsigargin and tunicamycin, also alter DR5 disulfide bonding in various cancer cell lines, and in some instances, DR5 mis-disulfide bonding is potentiated by overriding the integrated stress response (ISR) with inhibitors of the PERK kinase or the ISR inhibitor ISRIB. These observations indicate that the pattern of DR5 disulfide bonding functions as a sensor of ER stress and serves as an effector of proteotoxic stress by driving extrinsic apoptosis independently of extracellular ligands.</p><p><strong>Implications: </strong>Extreme ER stress triggers triage of transmembrane receptor production, whereby mitogenic receptors are downregulated and death receptors are simultaneously elevated.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"622-639"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11989202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}