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

mTORC2 Promotes Tumorigenesis via Lipid Synthesis.

Author information

1
Biozentrum, University of Basel, 4056 Basel, Switzerland.
2
Departments of Melanoma Medical Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
4
NCCR Chemical Biology, Department of Biochemistry, University of Geneva, 1211 Geneva, Switzerland.
5
Biozentrum, University of Basel, 4056 Basel, Switzerland. Electronic address: m.hall@unibas.ch.

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

PMID:
29232555
DOI:
10.1016/j.ccell.2017.11.011
[Indexed for MEDLINE]

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