[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-330055-105":59,"doc-detail-330055-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","prkcsh-contributes-to-tnfsf-resistance-by-extending-igf1r-half-life-and-activation-in-lung-cancer","PRKCSH contributes to TNFSF resistance by extending IGF1R half-life and activation in lung cancer","","Tumor necrosis factor superfamily (TNFSF) resistance drives tumor development and undermines antitumor immunity, yet the tumor-intrinsic regulators of the TNFSF response remain poorly understood. This study shows that PRKCSH (protein kinase C substrate 80K-H) abundance enhances oncogenic IGF1R activation, promoting TNFSF resistance in lung cancer. PRKCSH increases IGF1R expression, extends IGF1R half-life through direct interaction, and disrupts caspase activation to shift survival over cell death. PRKCSH loss also strengthens natural killer cell antitumor effects in a xenograft model, suggesting PRKCSH as a therapeutic target to improve NK-cell–based cancer therapy efficacy.",{"@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/prkcsh-contributes-to-tnfsf-resistance-by-extending-igf1r-half-life-and-activation-in-lung-cancer/330055/",{"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/prkcsh-contributes-to-tnfsf-resistance-by-extending-igf1r-half-life-and-activation-in-lung-cancer/330055.png","ImageObject",300,407,{"name":92,"@type":93},"Logic","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-10","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does PRKCSH play in TNFSF resistance in lung cancer?","Question",{"text":112,"@type":113},"PRKCSH abundance promotes oncogenic IGF1R activation and leads to TNFSF resistance in lung cancer cells. It does so by extending IGF1R half-life and sustaining pro-survival signaling.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does PRKCSH affect IGF1R and downstream cell-death pathways?",{"text":117,"@type":113},"PRKCSH interacts with IGF1R and extends its half-life. This PRKCSH–IGF1R axis impairs caspase-8 activation, increases Mcl-1 expression, and inhibits caspase-9, shifting the balance away from cell death toward survival.",{"name":119,"@type":110,"acceptedAnswer":120},"How does PRKCSH deficiency influence natural killer (NK) cell therapy?",{"text":121,"@type":113},"PRKCSH deficiency augments the antitumor effects of NK cells, particularly in a tumor xenograft IL-2Rg-deficient NOD/SCID (NIG) mouse model. The findings support PRKCSH as a potential target to improve NK-cell-based cancer therapy.","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},330055,1790172691,{"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":34,"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},1099513958762,"https://ap-avatar.wpscdn.com/avatar/1000023916a998db790?x-image-process=image/resize,m_fixed,w_180,h_180&k=1784791008015729253","[www.nature.com/emm](www.nature.com/emm)  \nARTICLE OPEN  \nPRKCSH contributes to TNFSF resistance by extending IGF1R half-life and activation in lung cancer  \nGu-Choul Shin 1,2 ✉, Hyeong Min Lee 3,4, Nayeon Kim1, Sang-Uk Seo 2, Kwang Pyo Kim 3,4 and Kyun-Hwan Kim 1 ✉  \n© The Author(s) 2024  \n|  |  |  |\n| --- | --- | --- |\n|  | Tumor necrosis factor superfamily (TNFSF) resistance contributes to the development and progression of tumors and resistance to various cancer therapies. Tumor-intrinsic alterations involved in the adaptation to the TNFSF response remain largely unknown. Here, we demonstrate that protein kinase C substrate 80K-H (PRKCSH) abundance in lung cancers boosts oncogenic IGF1R activation, leading to TNFSF resistance. PRKCSH abundance is correlated with IGF1R upregulation in lung cancer tissues. Specifically, PRKCSH interacts with IGF1R and extends its half-life. The PRKCSH-IGF1R axis in tumor cells impairs caspase-8 activation, increases Mcl-1 expression, and inhibits caspase-9, leading to an imbalance between cell death and survival. PRKCSH deficiency augmented the antitumor effects of natural killer (NK) cells, representative TNFSF effector cells, in a tumor xenograft IL-2Rg-deficient NOD/SCID (NIG) mouse model. Our data suggest that PRKCSH plays a critical role in TNFSF resistance and may be a potential target to improve |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| the efficacy of NK cell-based cancer therapy. |  |  |\n|  | Experimental & Molecular Medicine (2024) 56:192–209; [https://doi.org/10.1038/s12276-023-01](https://doi.org/10.1038/s12276-023-01)147-1 |  |\n|  |  |  |\n\nINTRODUCTION  \nTumor necrosis factor superfamily (TNFSF) resistance promotes tumor development and incapacitates the antitumor immune response1–4. Although several TNFSFs, including FasL, TNF-α, and TNF-related apoptosis-inducing ligand (TRAIL), have been identified as emerging cancer immunotherapeutic targets 5–7, most cancers are adapted to the TNFSF response, leading to an imbalance between cell death and survival; this renders them intractable, even against various cancer therapies such as immune checkpoint blockades and chemotherapeutics8,9. Sensitivity to the TNFSF response was initially thought to be a result of preferential expression of the individual TNFSF receptors in tumor cells10. However, TNFSF sensitivity in tumor cells was found to be more complex and is regulated at various levels of intracellular signaling11–14. Thus, an in-depth study of the common factors involved in tumor-intrinsic alterations is critical for developing novel approaches to restore sensitivity to the TNFSF response.  \nNatural killer (NK) cells contribute to spontaneous antitumor responses and are recognized as potent effector cells in cancer therapy15. Autologous or allogeneic NK cells are deemed safer effector cells in targeted cancer cell therapy than T cells because they preferentially target tumor cells without the need for prior sensitization or knowledge of specific tumor antigens16–18. NK cells exert their cytotoxic activity by inducing TNFSF expression3, 15, 19. Additionally, TNFSF is important for T and NK cellmediated cytotoxicity to antigen-negative tumor cells3, 15, 19. Cytotoxic T-cell and NK cell evasion by tumor cells is primarily dependent on TNFSF resistance but occurs independently of perforin-mediated killing20,21. Although promising antitumor  \neffects of NK cells have been reported, the underlying cellular mechanisms by which tumor cells adapt to NK cell-mediated antitumor immunity are still unclear.  \nProtein kinase C substrate 80K-H (PRKCSH), the glucosidase II beta subunit, is localized in the endoplasmic reticulum (ER) lumen, where it forms a complex with the glucosidase II alpha subunit and contributes to the folding and quality control of glycoproteins22,23. It also contributes to breast cancer progression and tumor resistance to EGFR inhibitors in non-small cell lung cancer24,25. Fur","cbCaiteYKhk2r3aW","https://ap.wps.com/l/cbCaiteYKhk2r3aW","pdf",9493914,18,"English","# Introduction\n## TNFSF resistance and cancer adaptation\n## Role of natural killer cells\n## PRKCSH background and rationale for study\n# Materials and Methods\n## Cell lines and reagents","[{\"question\":\"What role does PRKCSH play in TNFSF resistance in lung cancer?\",\"answer\":\"PRKCSH abundance promotes oncogenic IGF1R activation and leads to TNFSF resistance in lung cancer cells. It does so by extending IGF1R half-life and sustaining pro-survival signaling.\"},{\"question\":\"How does PRKCSH affect IGF1R and downstream cell-death pathways?\",\"answer\":\"PRKCSH interacts with IGF1R and extends its half-life. This PRKCSH–IGF1R axis impairs caspase-8 activation, increases Mcl-1 expression, and inhibits caspase-9, shifting the balance away from cell death toward survival.\"},{\"question\":\"How does PRKCSH deficiency influence natural killer (NK) cell therapy?\",\"answer\":\"PRKCSH deficiency augments the antitumor effects of NK cells, particularly in a tumor xenograft IL-2Rg-deficient NOD/SCID (NIG) mouse model. The findings support PRKCSH as a potential target to improve NK-cell-based cancer therapy.\"}]","PRKCSH contributes to TNFSF resistance by extending IGF1R half-life and activation in lung cancer | PDF",1789986809,45]