[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-330521-105":59,"doc-detail-330521-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","glutamine-mediated-epigenetic-regulation-of-cflip-underlies-resistance-to-trail-in-pancreatic-cancer","Glutamine-mediated epigenetic regulation of cFLIP underlies resistance to TRAIL in pancreatic cancer","","TRAIL is a promising anticancer ligand that induces apoptosis in cancer cells while sparing normal cells, yet pancreatic ductal adenocarcinoma (PDAC) often develops intrinsic or acquired resistance. This study shows that glutamine endows PDAC cells with TRAIL resistance via KDM4C-mediated epigenetic regulation of cFLIP. Glutaminolysis inhibition reduces cFLIP and promotes TRAIL-induced death-inducing signaling complex formation, whereas cFLIP overexpression or aKG supplementation rescues apoptosis. KDM4C knockdown sensitizes PDAC cells by decreasing cFLIP promoter-associated activating epigenetic control.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/glutamine-mediated-epigenetic-regulation-of-cflip-underlies-resistance-to-trail-in-pancreatic-cancer/330521/",{"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/glutamine-mediated-epigenetic-regulation-of-cflip-underlies-resistance-to-trail-in-pancreatic-cancer/330521.png","ImageObject",300,407,{"name":92,"@type":93},"Emma Wilson","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is TRAIL considered a promising anticancer agent, and what limits its success in PDAC?","Question",{"text":112,"@type":113},"TRAIL can specifically induce apoptosis in cancer cells with little to no toxicity to normal cells. Its intrinsic or acquired resistance in PDAC limits TRAIL-based therapies.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does glutamine influence TRAIL resistance in pancreatic cancer cells?",{"text":117,"@type":113},"Glutamine supports TRAIL resistance by enabling KDM4C-mediated epigenetic regulation of cFLIP. Blocking glutaminolysis lowers cFLIP and increases sensitivity to TRAIL.",{"name":119,"@type":110,"acceptedAnswer":120},"What role does cFLIP play in the response to TRAIL under glutamine deprivation?",{"text":121,"@type":113},"Inhibition of glutaminolysis significantly reduces cFLIP, which allows TRAIL to trigger death-inducing signaling complex formation and apoptosis. Overexpressing cFLIP rescues PDAC cells from apoptosis caused by TRAIL and glutamine deprivation.","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},330521,1791069996,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"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,"preview_page_count":4},3848291630094,"https://eur-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","[www.nature.com/emm](www.nature.com/emm)  \nARTICLE OPEN   \nGlutamine-mediated epigenetic regulation of cFLIP underlies resistance to TRAIL in pancreatic cancer  \nJi Hye Kim 1, Jinyoung Lee 1, Se Seul Im1, Boyun Kim1, Eun-Young Kim1, Hyo-Jin Min1, Jinbeom Heo2, Eun-Ju Chang 1  \nKyung-Chul Choi1, Dong-Myung Shin 2 and Jaekyoung Son1 ✉ ,  \n© The Author(s) 2024  \n\n|  | Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because it kills cancer cells while sparing normal cells. However, many cancers, including pancreatic ductal adenocarcinoma (PDAC), exhibit intrinsic or acquired resistance to TRAIL, and the molecular mechanisms underlying TRAIL resistance in cancers, particularly in PDAC, remain unclear. In this study, we demonstrated that glutamine (Gln) endows PDAC cells with resistance to TRAIL through KDM4C-mediated epigenetic regulation of cFLIP. Inhibition of glutaminolysis significantly reduced the cFLIP level, leading to TRAIL-mediated formation of deathinducing signaling complexes. Overexpression of cFLIP dramatically rescued PDAC cells from TRAIL/Gln deprivation-induced apoptosis. Alpha-Ketoglutarate (aKG) supplementation significantly reversed the decrease in the cFLIP level induced by glutaminolysis inhibition and rescued PDAC cells from TRAIL/Gln deprivation-induced apoptosis. Knockdown of glutamicoxaloacetic transaminase 2, which facilitates the conversion of oxaloacetate and glutamate into aspartate and aKG, decreased aKG production and the cFLIP level and activated TRAIL-induced apoptosis. AKG-mediated epigenetic regulation was necessary for maintaining a high level of cFLIP. Glutaminolysis inhibition increased the abundance of H3K9me3 in the cFLIP promoter, indicating that Gln-derived aKG production is important for Jumonji-domain histone demethylase (JHDM)-mediated cFLIP regulation. The JHDM KDM4C regulated cFLIP expression by binding to its promoter, and KDM4C knockdown sensitized PDAC cells to TRAILinduced apoptosis. The present findings suggest that Gln-derived aKG production is required for KDM4C-mediated epigenetic |  |\n| --- | --- | --- |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| regulation of cFLIP, which leads to resistance to TRAIL. |  |  |\n|  | Experimental & Molecular Medicine (2024) 56:1013–1026; [https://doi.org/10.1038/s12276-024-01231-0](https://doi.org/10.1038/s12276-024-01231-0) |  |\n|  |  |  |\n\nINTRODUCTION  \nPancreatic ductal adenocarcinoma (PDAC) is the most prevalent neoplastic tumor of the pancreas; it accounts for 90% of all pancreatic cancers and is an extremely aggressive tumor with an expected 5 year survival rate of 8%1. Patients with PDAC have a dismal prognosis because the disease is often diagnosed at a late stage, and surgical resection is no longer possible. In addition, PDAC often exhibits resistance to chemotherapy and radiotherapy2, resulting in one of the lowest survival rates among all malignancies; moreover, the 5 year survival rate of PDAC patients has improved little in recent decades. The poor survival rate of patients with PDAC and the lack of effective treatments underscore the need to improve our understanding of the molecular mechanisms underlying tumor resistance to apoptotic cell death to identify effective therapies for PDAC.  \nApoptosis is a regulated programmed cell death process that is distinct from other forms of cell death, such as autophagy and necrosis. It eliminates cells that are no longer needed or are damaged, thereby maintaining homeostasis in multicellular organisms. The regulation of cell death is critical, and inappropriate apoptosis contributes to the development of many diseases, such as neurodegenerative diseases, autoimmune disorders, and  \nmany types of cancer3,4. Certain oncogenic mutations result in inactivation of apoptosis during tumor initiation and progression, and many studies have aimed to develo","cbCainziz9TpzAgs","https://ap.wps.com/l/cbCainziz9TpzAgs","pdf",4900672,14,"English","# Introduction\n# Experimental & Molecular Medicine","[{\"question\":\"Why is TRAIL considered a promising anticancer agent, and what limits its success in PDAC?\",\"answer\":\"TRAIL can specifically induce apoptosis in cancer cells with little to no toxicity to normal cells. Its intrinsic or acquired resistance in PDAC limits TRAIL-based therapies.\"},{\"question\":\"How does glutamine influence TRAIL resistance in pancreatic cancer cells?\",\"answer\":\"Glutamine supports TRAIL resistance by enabling KDM4C-mediated epigenetic regulation of cFLIP. Blocking glutaminolysis lowers cFLIP and increases sensitivity to TRAIL.\"},{\"question\":\"What role does cFLIP play in the response to TRAIL under glutamine deprivation?\",\"answer\":\"Inhibition of glutaminolysis significantly reduces cFLIP, which allows TRAIL to trigger death-inducing signaling complex formation and apoptosis. Overexpressing cFLIP rescues PDAC cells from apoptosis caused by TRAIL and glutamine deprivation.\"}]","Glutamine-mediated epigenetic regulation of cFLIP underlies resistance to TRAIL in pancreatic cancer | PDF",1789989267,35]