mTORC2 通过脂质合成促进肿瘤发生。

mTORC2 Promotes Tumorigenesis via Lipid Synthesis.

机构信息

Biozentrum, University of Basel, 4056 Basel, Switzerland.

Departments of Melanoma Medical Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

出版信息

Cancer Cell. 2017 Dec 11;32(6):807-823.e12. doi: 10.1016/j.ccell.2017.11.011.

DOI:10.1016/j.ccell.2017.11.011

PMID:29232555

Abstract

Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis. Inhibition of fatty acid or sphingolipid synthesis prevented tumor development, indicating a causal effect in tumorigenesis. Increased levels of cardiolipin were associated with tubular mitochondria and enhanced oxidative phosphorylation. Furthermore, increased lipogenesis correlated with elevated mTORC2 activity and HCC in human patients. Thus, mTORC2 promotes cancer via formation of lipids essential for growth and energy production.

摘要

哺乳动物雷帕霉素靶蛋白（mTOR）失调会促进癌症，但相关的潜在机制尚不清楚。我们描述了一种 mTOR 驱动的小鼠模型，该模型表现出肝脂肪变性进展为肝细胞癌（HCC）。纵向蛋白质组学、脂质组学和代谢组学分析表明，肝 mTORC2 促进脂肪酸和脂质的从头合成，导致脂肪变性和肿瘤发展。特别是，mTORC2 刺激鞘脂（葡萄糖脑苷脂）和甘油磷脂（心磷脂）的合成。抑制脂肪酸或鞘脂合成可防止肿瘤发展，表明其在肿瘤发生中具有因果关系。心磷脂水平的升高与管状线粒体和增强的氧化磷酸化有关。此外，脂肪生成的增加与 mTORC2 活性的升高和人类患者的 HCC 相关。因此，mTORC2 通过形成对生长和能量产生至关重要的脂质来促进癌症。