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PARP inhibitors such as Olaparib benefit homologous recombination repair (HRR)-deficient tumors, yet resistance commonly emerges from DNA repair restoration. This study investigates SLX1, a catalytic subunit of the SLX1-SLX4 endonuclease complex, and shows SLX1 as a prognostic factor and potential target to enhance PARPi efficacy in advanced disease.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/slx1-silencing-overcomes-olaparib-resistance-in-metastatic-castration-resistant-prostate-cancer-by-disrupting-slx4-mediated-dna-repair-complexes/373606/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/slx1-silencing-overcomes-olaparib-resistance-in-metastatic-castration-resistant-prostate-cancer-by-disrupting-slx4-mediated-dna-repair-complexes/373606.png","ImageObject",300,407,{"name":92,"@type":93},"McQueen","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What therapeutic problem does the study focus on?","Question",{"text":112,"@type":113},"The study targets resistance to PARP inhibitors, specifically Olaparib, in metastatic castration-resistant prostate cancer (mCRPC).","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was SLX1 investigated in relation to Olaparib resistance?",{"text":117,"@type":113},"The work used TCGA for expression and survival analyses and employed the CRPC cell line DU145 (with BRCA1/BRCA2 mutations) for in vitro and in vivo experiments.",{"name":119,"@type":110,"acceptedAnswer":120},"What happens when SLX1 is silenced in Olaparib-resistant cells?",{"text":121,"@type":113},"SLX1 knockdown using shRNA enhances Olaparib sensitivity, reduces colony formation, and increases DNA damage and apoptosis in DU145 and Olaparib-resistant DU145-OR cells.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},373606,1790831701,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},5909890329169,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","RESEARCH PAPER  \nSLX1 silencing overcomes Olaparib resistance in metastatic castration-resistant prostate cancer by disrupting SLX4-mediated DNA repair complexes  \nXin Zhaoa,b,c, Shiyun Fengb, Xiaoping Nitieb, Shibu Muluob, and Yi Lei b,c,d,e  \naDepartment of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China; bDepartment of Urology, The First People’s Hospital of Yuexi County, Liangshan Prefecture, China; cSichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, China; dDepartment of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China; eMetabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, Sichuan, China  \nABSTRACT  \nPurpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a significant therapeutic challenge and a leading cause of cancer-related mortality in men. PARP inhibitors like Olaparib are effective in homologous recombination repair (HRR)-deficient tumors, but resistance often arises through DNA repair restoration. This study explores the role of the structure-specific endonuclease subunit SLX1, a catalytic subunit of the SLX1-SLX4 endonuclease complex, in Olaparib resistance.  \nMethods: Data from The Cancer Genome Atlas (TCGA) were used for expression and survival analyses. The CRPC cell line DU145, which harbors BRCA1 and BRCA2 mutations, was used as a cell model for both in vitro and in vivo studies.  \nResults: Elevated SLX1A expression in prostate cancer tissues was associated with significantly reduced progression-free and overall survival. SLX1 protein was upregulated in androgen-resistant prostate cancer cell lines (DU145, 22RV1, PC3) and further increased in Olaparib-resistant DU145 (DU145-OR) cells. Silencing SLX1 via shRNA enhanced Olaparib sensitivity, reducing colony formation and increasing DNA damage and apoptosis in DU145 and DU145-OR cells. Mechanistically, SLX1 knockdown disrupted SLX4 interactions with critical DNA repair proteins (ERCC1-XPF, PLK1, and TOPBP1), impairing DNA repair complex stability. In vivo, SLX1-silenced DU145 xenografts treated with Olaparib showed significantly reduced tumor growth with decreased Ki-67 expression and increased apoptosis/necrosis compared to controls.  \nConclusion: This study highlights SLX1 as both a prognostic marker and potential therapeutic target to enhance PARPi efficacy in advanced prostate cancer. Targeting SLX1 may be a promising strategy to overcome Olaparib resistance in mCRPC patients with homologous recombination deficiency.  \nARTICLE HISTORY  \nReceived 26 March 2025 Revised 31 July 2025 Accepted 4 August 2025  \nKEYWORDS  \nmCRPC; SLX1; parpi; Olaparib  \nIntroduction  \nProstate cancer (PCa) is one of the most common malignancies in men, with its incidence and mortality rates continuing to rise worldwide. 1 Radical prostatectomy or radiation therapy can effectively treat earlystage prostate cancer. Nevertheless, in China, only 42% of newly diagnosed patients have localized earlystage prostate cancer, with 28% presenting with locally advanced disease and 30% exhibiting distant metastasis.2–4  \nFor metastatic prostate cancer patients, androgen deprivation therapy (ADT) remains the first-line treatment. However, most hormone-sensitive prostate cancer patients, after receiving standard ADT treatment, progress to castration-resistant prostate cancer (CRPC) within 18–24 months.5,6 Furthermore, the vast majority of CRPC cases will eventually progress to metastatic CRPC (mCRPC) .5,6 Current treatment options for mCRPC include chemotherapy primarily with taxane-based drugs, new second-line endocrine therapies, radionuclide therapy, and the recently approved PARP inhibitors (PARPi, such as Olaparib and Rucaparib). Olaparib has been approved for treating mCRPC patients with any homologous  \nCONTACT Yi Lei  [leiyilyfy@163.com](leiyilyfy@163.com)  Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Me","cbCaiudstXVqSNyj","https://ap.wps.com/l/cbCaiudstXVqSNyj","pdf",3691811,14,"English","# Abstract\n# Introduction\n# Methods and Models\n# Results\n## Clinical Association and Expression Changes\n## Functional Effects of SLX1 Silencing\n## Mechanistic Disruption of DNA Repair Complexes\n## In Vivo Tumor Response\n# Conclusion","[{\"question\":\"What therapeutic problem does the study focus on?\",\"answer\":\"The study targets resistance to PARP inhibitors, specifically Olaparib, in metastatic castration-resistant prostate cancer (mCRPC).\"},{\"question\":\"How was SLX1 investigated in relation to Olaparib resistance?\",\"answer\":\"The work used TCGA for expression and survival analyses and employed the CRPC cell line DU145 (with BRCA1/BRCA2 mutations) for in vitro and in vivo experiments.\"},{\"question\":\"What happens when SLX1 is silenced in Olaparib-resistant cells?\",\"answer\":\"SLX1 knockdown using shRNA enhances Olaparib sensitivity, reduces colony formation, and increases DNA damage and apoptosis in DU145 and Olaparib-resistant DU145-OR cells.\"}]","SLX1 silencing overcomes Olaparib resistance in metastatic castration-resistant prostate cancer by disrupting SLX4-mediated DNA repair complexes | PDF",1790200009,35]