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mTORC2 Promotes Tumorigenesis via Lipid Synthesis.

Cancer cell (2017-12-13)
Yakir Guri, Marco Colombi, Eva Dazert, Sravanth K Hindupur, Jason Roszik, Suzette Moes, Paul Jenoe, Markus H Heim, Isabelle Riezman, Howard Riezman, Michael N Hall
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.

MATERIALS
Product Number
Brand
Product Description

Avanti
17:0-14:1 PS, Avanti Research - A Croda Brand LM1304, methanol solution
Avanti
14:0 Cardiolipin (ammonium salt), 1′,3′-bis[1,2-dimyristoyl-sn-glycero-3-phospho]-glycerol (ammonium salt), chloroform
Sigma-Aldrich
Ribonuclease A from bovine pancreas, Type II-A, ≥60% (SDS-PAGE), >= 60 Kunitz units/mg protein
Sigma-Aldrich
L-Glutamine solution, 200 mM, solution, sterile-filtered, BioXtra, suitable for cell culture
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D-erythro-Dihydrosphingosine, ≥98%
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Penicillin-Streptomycin, Solution stabilized, with 10,000 units penicillin and 10 mg streptomycin/mL, 0.1 μm filtered, BioReagent, suitable for cell culture
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Myriocin from Mycelia sterilia, ≥98% (HPLC), powder
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C75, ≥98% (HPLC), powder
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Urease from Canavalia ensiformis (Jack bean), Type IX, powder, 50,000-100,000 units/g solid
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Anti-Actin Antibody, clone C4, ascites fluid, clone C4, Chemicon®
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17:0-14:1 PI, Avanti Research - A Croda Brand LM1504, methanol solution
Avanti
17:0-14:1 PE, Avanti Research - A Croda Brand
Roche
5-Bromo-2′-deoxy-uridine Labeling and Detection Kit II, sufficient for ≤100 tests, storage temp.:-20°C