Integration of glucose and cardiolipin anabolism confers radiation resistance of HCC.
Integration of glucose and cardiolipin anabolism confers radiation resistance of HCC.
复制标题
葡萄糖和心磷脂合成代谢的整合赋予肝细胞癌的放射抗性
DOI：
10.1002/hep.32177
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发表时间：
2022-06
期刊：
影响因子：
13.5
通讯作者：
Wu, Dehua
中科院分区：
文献类型：
--
作者：
Fang, Yuan;Zhan, Yizhi;Xie, Yuwen;Du, Shisuo;Chen, Yuhan;Zeng, Zhaochong;Zhang, Yaowei;Chen, Keli;Wang, Yongjia;Liang, Li;Ding, Yi;Wu, Dehua
由于耐药性导致的对电离辐射（IR）的不良反应仍然是临床挑战。代谢改变代表了几乎所有类型癌症的定义特征。然而，在肝细胞癌（HCC）中，放射抗性如何与代谢重编程联系在一起仍然是难以捉摸的。鉴定不同HCC细胞的基线辐射反应性，并产生具有获得性放射抗性的细胞。通过进行蛋白质组学、代谢组学、代谢通量和其他功能研究，我们描述了一种介导HCC辐射抗性的代谢表型，由此增加的葡萄糖通量导致辐射抗性HCC细胞中的葡萄糖成瘾，并相应增加甘油磷脂生物合成以提高心磷脂水平。心磷脂的积累通过抑制细胞色素c释放来启动细胞凋亡而减弱IR的有效性。从机制上讲，哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）信号转导介导的低氧诱导因子-1 α（HIF-1α）和固醇调节元件结合蛋白-1（SREBP 1）的翻译控制重塑了这种代谢级联反应。靶向mTORC 1或葡萄糖合成心磷脂，结合IR，强烈减少肿瘤负荷。最后，葡萄糖代谢的激活预示着癌症患者对放射治疗的不良反应。我们证明了放射抵抗和代谢整合之间的联系，并建议代谢拆解肿瘤的放射抵抗特征可能为HCC的放射治疗提供潜在的组合方法。
Poor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of cancers. However, how radioresistance is linked to metabolic reprogramming remains elusive in hepatocellular carcinoma (HCC). Baseline radiation responsiveness of different HCC cells were identified and cells with acquired radio‐resistance were generated. By performing proteomics, metabolomics, metabolic flux, and other functional studies, we depicted a metabolic phenotype that mediates radiation resistance in HCC, whereby increased glucose flux leads to glucose addiction in radioresistant HCC cells and a corresponding increase in glycerophospholipids biosynthesis to enhance the levels of cardiolipin. Accumulation of cardiolipin dampens the effectiveness of IR by inhibiting cytochrome c release to initiate apoptosis. Mechanistically, mammalian target of rapamycin complex 1 (mTORC1) signaling‐mediated translational control of hypoxia inducible factor‐1α (HIF‐1α) and sterol regulatory element‐binding protein‐1 (SREBP1) remodels such metabolic cascade. Targeting mTORC1 or glucose to cardiolipin synthesis, in combination with IR, strongly diminishes tumor burden. Finally, activation of glucose metabolism predicts poor response to radiotherapy in cancer patients. We demonstrate a link between radiation resistance and metabolic integration and suggest that metabolically dismantling the radioresistant features of tumors may provide potential combination approaches for radiotherapy in HCC.
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