2. Academic Validation
  3. CRLF1 bridges AKT and mTORC2 through SIN1 to inhibit pyroptosis and enhance chemo-resistance in ovarian cancer

CRLF1 bridges AKT and mTORC2 through SIN1 to inhibit pyroptosis and enhance chemo-resistance in ovarian cancer

  • Cell Death Dis. 2024 Sep 10;15(9):662. doi: 10.1038/s41419-024-07035-4.
Cong Xiang 1,  Li Chen 1,  Shilei Zhu 2,  Yue Chen 1,  Haodong Huang 1,  Chunmao Yang 3,  Yugang Chi 1,  Yanzhou Wang 3,  Yunlong Lei 4 5,  Xiongwei Cai 6
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, China.
  • 2 Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.
  • 3 Department of Gynecology, Southwest Hospital, Chongqing, China.
  • 4 Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
  • 5 Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
  • 6 Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, China. xiongweicai@126.com.
PMID: 39256356 DOI: 10.1038/s41419-024-07035-4
Abstract

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.

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