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CRLF1 通过 SIN1 桥接 AKT 和 mTORC2 抑制卵巢癌细胞焦亡并增强化疗耐药性。

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

机构信息

Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children (Women and Children's Hospital of Chongqing Medical University), Chongqing, China.

Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.

出版信息

Cell Death Dis. 2024 Sep 10;15(9):662. doi: 10.1038/s41419-024-07035-4.

DOI:10.1038/s41419-024-07035-4
PMID:39256356
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11387770/
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.

摘要

卵巢癌是全球第二大导致妇科癌症死亡的原因，其面临着化疗耐药的挑战，这是一个重大障碍。焦亡是一种由 GSDMDs 介导的与炎症相关的程序性细胞死亡，当失调时会影响化疗耐药性。然而，焦亡与卵巢癌化疗耐药之间的机制尚不清楚。我们发现细胞因子受体样因子 1（CRLF1）是 mTORC2 的一个新组成部分，通过增强 AKT 和应激激活蛋白激酶相互作用蛋白 1（SIN1）之间的相互作用来增强 AKT Ser473 磷酸化，从而抑制丝裂原活化蛋白激酶激酶激酶 5（ASK1）-c-Jun N-末端激酶（JNK）-半胱天冬酶-3-GSDME 焦亡途径，并最终赋予化疗耐药性。高表达 CRLF1 的肿瘤对 AKT 抑制敏感，但对顺铂耐受。值得注意的是，表达结合缺陷的 CRLF1 变体破坏了 AKT-SIN1 相互作用，促进了焦亡和化疗增敏。因此，CRLF1 通过调节 AKT/SIN1 依赖性焦亡来严格调控卵巢癌的化疗耐药性。结合缺陷的 CRLF1 变体可被开发为肿瘤特异性多肽药物，以增强卵巢癌的化疗效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/f70829f14b73/41419_2024_7035_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/880a9229ebf8/41419_2024_7035_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/c8c3ba99d5f4/41419_2024_7035_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/f6fc1acecab6/41419_2024_7035_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/61e75b3abd92/41419_2024_7035_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/7ff8a80bd5da/41419_2024_7035_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/1f68c4913a77/41419_2024_7035_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/82db24eb6d96/41419_2024_7035_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/f70829f14b73/41419_2024_7035_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/880a9229ebf8/41419_2024_7035_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/c8c3ba99d5f4/41419_2024_7035_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/f6fc1acecab6/41419_2024_7035_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/61e75b3abd92/41419_2024_7035_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/7ff8a80bd5da/41419_2024_7035_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/1f68c4913a77/41419_2024_7035_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/82db24eb6d96/41419_2024_7035_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70bf/11387770/f70829f14b73/41419_2024_7035_Fig8_HTML.jpg

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Neoadjuvant chemotherapy followed by interval debulking surgery for advanced epithelial ovarian cancer: GOTIC-019 study.新辅助化疗后间隔减瘤手术治疗晚期上皮性卵巢癌：GOTIC-019 研究。
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用于治疗癌症的各种烟酰胺磷酸核糖转移酶（NAMPT）抑制剂的综述。
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