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肿瘤再生细胞通过依赖 PCK2 的磷脂重塑来逃避铁死亡。

Tumor-repopulating cells evade ferroptosis via PCK2-dependent phospholipid remodeling.

机构信息

State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.

出版信息

Nat Chem Biol. 2024 Oct;20(10):1341-1352. doi: 10.1038/s41589-024-01612-6. Epub 2024 May 8.

DOI:10.1038/s41589-024-01612-6
PMID:38720107
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11427348/
Abstract

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679) in multiple preclinical models, we discovered that higher PCK2 and pACSL4(T679) levels are correlated with better response to chemotherapy and radiotherapy as well as lower distant metastasis in nasopharyngeal carcinoma cohorts.

摘要

干细胞样癌细胞是否通过避免铁死亡来介导治疗耐药性尚不清楚。在这项研究中，我们使用软纤维蛋白凝胶培养系统发现，具有干细胞样癌细胞特征的肿瘤再生细胞（TRC）通过降低铁死亡敏感性来抵抗化疗和放疗。在机制上，通过定量质谱和脂质组学分析，我们确定线粒体代谢激酶 PCK2 磷酸化并激活 ACSL4 以驱动铁死亡相关的磷脂重塑。TRC 下调 PCK2 的表达，使自身处于结构上的铁死亡抵抗状态。值得注意的是，除了在多个临床前模型中证实 PCK2-pACSL4(T679)的作用外，我们还发现鼻咽癌队列中更高的 PCK2 和 pACSL4(T679)水平与对化疗和放疗的更好反应以及更低的远处转移相关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/6cb4a2a71d15/41589_2024_1612_Fig16_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/6cb4a2a71d15/41589_2024_1612_Fig16_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/c9a583152fd1/41589_2024_1612_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/2477431ce0cf/41589_2024_1612_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/214badd4b4d1/41589_2024_1612_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/46d66e50a4a0/41589_2024_1612_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/87a7b6f9efe1/41589_2024_1612_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/459466596a6f/41589_2024_1612_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/7881e406c601/41589_2024_1612_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/f0091483641d/41589_2024_1612_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/fbc30f464984/41589_2024_1612_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/80b4e054b30f/41589_2024_1612_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/2166da2cf14e/41589_2024_1612_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/8e65b85ecaaa/41589_2024_1612_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/b055572b9024/41589_2024_1612_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/5771e6629853/41589_2024_1612_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/3dc362f7f62e/41589_2024_1612_Fig15_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f59/11427348/6cb4a2a71d15/41589_2024_1612_Fig16_ESM.jpg

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本文引用的文献

[1]
AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer.

Nat Commun. 2023-9-5

[2]
Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones.

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Redox Biol. 2023-5

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