mTORC2 Promotes Tumorigenesis via Lipid Synthesis - PubMed

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• PMID: 29232555
• DOI: 10.1016/j.ccell.2017.11.011

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mTORC2 Promotes Tumorigenesis via Lipid Synthesis

Yakir Guri et al. Cancer Cell. 2017.

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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.

Keywords: NAFLD; NASH; cardiolipin; glycosphingolipid; hepatocellular carcinoma; hepatosteatosis; mTOR; mitochondria; oxidative phosphorylation; sphingolipid.

Comment in

• mTORC2-Driven Lipid Synthesis Promotes Liver Tumorigenesis.

  [No authors listed] [No authors listed] Cancer Discov. 2018 Feb;8(2):OF9. doi: 10.1158/2159-8290.CD-RW2017-237. Epub 2017 Dec 21. Cancer Discov. 2018. PMID: 29269347

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