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STIM1通过减轻肝癌中的铁死亡来促进对索拉非尼的获得性耐药。

STIM1 promotes acquired resistance to sorafenib by attenuating ferroptosis in hepatocellular carcinoma.

作者信息

Ren Ran, Chen Yu, Zhou Yu, Shen Luyao, Chen Yang, Lei Juan, Wang Jingchun, Liu Xudong, Zhang Nan, Zhou Dongqin, Zhao Huakan, Li Yongsheng

机构信息

Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing 400044, China.

Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing 400030, China.

出版信息

Genes Dis. 2024 Mar 28;11(6):101281. doi: 10.1016/j.gendis.2024.101281. eCollection 2024 Nov.

DOI:10.1016/j.gendis.2024.101281
PMID:39281833
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11402164/
Abstract

Dysregulated calcium (Ca) signaling pathways are associated with tumor cell death and drug resistance. In non-excitable cells, such as hepatocellular carcinoma (HCC) cells, the primary pathway for Ca influx is through stromal interaction molecule 1 (STIM1)-mediated store-operated calcium entry (SOCE). Previous studies have demonstrated the involvement of STIM1-mediated SOCE in processes such as genesis, metastasis, and stem cell self-renewal of HCC. However, it remains unclear whether STIM1-mediated SOCE plays a role in developing acquired resistance to sorafenib in HCC patients. In this study, we established acquired sorafenib-resistant (SR) HCC cell lines by intermittently exposing them to increasing concentrations of sorafenib. Our results showed higher levels of STIM1 and stronger SOCE in SR cells compared with parental cells. Deleting STIM1 significantly enhanced sensitivity to sorafenib in SR cells, while overexpressing STIM1 promoted SR by activating SOCE. Mechanistically, STIM1 increased the transcription of SLC7A11 through the SOCE-CaN-NFAT pathway. Subsequently, up-regulated SLC7A11 increased glutathione synthesis, resulting in ferroptosis insensitivity and SR. Furthermore, combining the SOCE inhibitor SKF96365 with sorafenib significantly improved the sensitivity of SR cells to sorafenib both and . These findings suggest a potential strategy to overcome acquired resistance to sorafenib in HCC cells.

摘要

钙（Ca）信号通路失调与肿瘤细胞死亡和耐药性相关。在非兴奋性细胞中，如肝癌（HCC）细胞，Ca内流的主要途径是通过基质相互作用分子1（STIM1）介导的储存式钙内流（SOCE）。先前的研究已证明STIM1介导的SOCE参与HCC的发生、转移和干细胞自我更新等过程。然而，STIM1介导的SOCE在HCC患者对索拉非尼获得性耐药的发生中是否起作用仍不清楚。在本研究中，我们通过将HCC细胞间歇性暴露于浓度递增的索拉非尼中，建立了获得性索拉非尼耐药（SR）HCC细胞系。我们的结果显示，与亲代细胞相比，SR细胞中STIM1水平更高，SOCE更强。敲除STIM1显著增强了SR细胞对索拉非尼的敏感性，而过度表达STIM1则通过激活SOCE促进了SR。机制上，STIM1通过SOCE-CaN-NFAT途径增加了SLC7A11的转录。随后，上调的SLC7A11增加了谷胱甘肽合成，导致铁死亡不敏感和SR。此外，将SOCE抑制剂SKF96365与索拉非尼联合使用，显著提高了SR细胞对索拉非尼的敏感性。这些发现提示了一种克服HCC细胞对索拉非尼获得性耐药的潜在策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/d1a8350ae08f/figs6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/d1a8350ae08f/figs6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/9936334ef39c/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/0acca1b757f4/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/b29c00eb42a8/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/9656605727a8/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/d0655a474e3a/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/a7e14cd01cda/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/c9e19e20540b/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/6f400d730004/figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/f01505221e82/figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/4696098f228d/figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/ccc306126932/figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/a09459be7b5c/figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3042/11402164/d1a8350ae08f/figs6.jpg

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Cell Metab. 2023 Jan 3;35(1):84-100.e8. doi: 10.1016/j.cmet.2022.09.021. Epub 2022 Oct 17.
2
Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications.铁死亡研究十周年：新兴机制、生理功能与治疗应用
Cell. 2022 Jul 7;185(14):2401-2421. doi: 10.1016/j.cell.2022.06.003.
3
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4
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CA Cancer J Clin. 2022 Jan;72(1):7-33. doi: 10.3322/caac.21708. Epub 2022 Jan 12.
5
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