Cong Xiang, Li Chen, Shilei Zhu, Yue Chen, Haodong Huang, Chunmao Yang, Yugang Chi, Yanzhou Wang, Yunlong Lei, Xiongwei Cai
{"title":"CRLF1 通过 SIN1 连接 AKT 和 mTORC2,从而抑制卵巢癌的化疗耐受性并增强其热休克功能","authors":"Cong Xiang, Li Chen, Shilei Zhu, Yue Chen, Haodong Huang, Chunmao Yang, Yugang Chi, Yanzhou Wang, Yunlong Lei, Xiongwei Cai","doi":"10.1038/s41419-024-07035-4","DOIUrl":null,"url":null,"abstract":"<p>Ovarian cancer, the second most leading cause of gynecologic cancer mortality worldwide, is challenged by chemotherapy resistance, presenting a significant hurdle. Pyroptosis, an inflammation-linked programmed cell death mediated by gasdermins, has been shown to impact chemoresistance when dysregulated. However, the mechanisms connecting pyroptosis to chemotherapy resistance in ovarian cancer are unclear. We found that cytokine receptor-like factor 1 (CRLF1) is a novel component of mTORC2, enhancing AKT Ser473 phosphorylation through strengthening the interaction between AKT and stress-activated protein kinase interacting protein 1 (SIN1), which in turn inhibits the mitogen-activated protein kinase kinase kinase 5 (ASK1)-JNK-caspase-3-gasdermin E pyroptotic pathway and ultimately confers chemoresistance. High CRLF1-expressing tumors showed sensitivity to AKT inhibition but tolerance to cisplatin. Remarkably, overexpression of binding-defective CRLF1 variants impaired AKT-SIN1 interaction, promoting pyroptosis and chemosensitization. Thus, CRLF1 critically regulates chemoresistance in ovarian cancer by modulating AKT/SIN1-dependent pyroptosis. Binding-defective CRLF1 variants could be developed as tumor-specific polypeptide drugs to enhance chemotherapy for ovarian cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1000,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"CRLF1 bridges AKT and mTORC2 through SIN1 to inhibit pyroptosis and enhance chemo-resistance in ovarian cancer\",\"authors\":\"Cong Xiang, Li Chen, Shilei Zhu, Yue Chen, Haodong Huang, Chunmao Yang, Yugang Chi, Yanzhou Wang, Yunlong Lei, Xiongwei Cai\",\"doi\":\"10.1038/s41419-024-07035-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Ovarian cancer, the second most leading cause of gynecologic cancer mortality worldwide, is challenged by chemotherapy resistance, presenting a significant hurdle. Pyroptosis, an inflammation-linked programmed cell death mediated by gasdermins, has been shown to impact chemoresistance when dysregulated. However, the mechanisms connecting pyroptosis to chemotherapy resistance in ovarian cancer are unclear. We found that cytokine receptor-like factor 1 (CRLF1) is a novel component of mTORC2, enhancing AKT Ser473 phosphorylation through strengthening the interaction between AKT and stress-activated protein kinase interacting protein 1 (SIN1), which in turn inhibits the mitogen-activated protein kinase kinase kinase 5 (ASK1)-JNK-caspase-3-gasdermin E pyroptotic pathway and ultimately confers chemoresistance. High CRLF1-expressing tumors showed sensitivity to AKT inhibition but tolerance to cisplatin. Remarkably, overexpression of binding-defective CRLF1 variants impaired AKT-SIN1 interaction, promoting pyroptosis and chemosensitization. Thus, CRLF1 critically regulates chemoresistance in ovarian cancer by modulating AKT/SIN1-dependent pyroptosis. Binding-defective CRLF1 variants could be developed as tumor-specific polypeptide drugs to enhance chemotherapy for ovarian cancer.</p>\",\"PeriodicalId\":9734,\"journal\":{\"name\":\"Cell Death & Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.1000,\"publicationDate\":\"2024-09-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Death & Disease\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s41419-024-07035-4\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death & Disease","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41419-024-07035-4","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
CRLF1 bridges AKT and mTORC2 through SIN1 to inhibit pyroptosis and enhance chemo-resistance in ovarian cancer
Ovarian cancer, the second most leading cause of gynecologic cancer mortality worldwide, is challenged by chemotherapy resistance, presenting a significant hurdle. Pyroptosis, an inflammation-linked programmed cell death mediated by gasdermins, has been shown to impact chemoresistance when dysregulated. However, the mechanisms connecting pyroptosis to chemotherapy resistance in ovarian cancer are unclear. We found that cytokine receptor-like factor 1 (CRLF1) is a novel component of mTORC2, enhancing AKT Ser473 phosphorylation through strengthening the interaction between AKT and stress-activated protein kinase interacting protein 1 (SIN1), which in turn inhibits the mitogen-activated protein kinase kinase kinase 5 (ASK1)-JNK-caspase-3-gasdermin E pyroptotic pathway and ultimately confers chemoresistance. High CRLF1-expressing tumors showed sensitivity to AKT inhibition but tolerance to cisplatin. Remarkably, overexpression of binding-defective CRLF1 variants impaired AKT-SIN1 interaction, promoting pyroptosis and chemosensitization. Thus, CRLF1 critically regulates chemoresistance in ovarian cancer by modulating AKT/SIN1-dependent pyroptosis. Binding-defective CRLF1 variants could be developed as tumor-specific polypeptide drugs to enhance chemotherapy for ovarian cancer.
期刊介绍:
Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism.
Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following:
Experimental medicine
Cancer
Immunity
Internal medicine
Neuroscience
Cancer metabolism