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Mol Cell. 2017 Jul 6;67(1):128-138.e7. doi: 10.1016/j.molcel.2017.05.030. Epub 2017 Jun 22.

mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT.

Author information

1
Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
2
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA; UCLA Metabolomics Center, Los Angeles, CA 90095, USA.
4
Department of Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA.
5
Department of Molecular and Medical Pharmacology, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA; Medical Scientist Training Program, David Geffen UCLA School of Medicine, Los Angeles, CA 90095, USA; Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
6
Division of Neurological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.
7
Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
8
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
9
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
10
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
11
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093 USA.
12
Department of Pharmacology, UCSD School of Medicine, La Jolla, CA 92093, USA; Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093 USA.
13
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pathology, UCSD School of Medicine, La Jolla, CA 92093 USA; Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093 USA. Electronic address: pmischel@ucsd.edu.

Abstract

Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian target of rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation into glutathione, linking growth factor receptor signaling with amino acid uptake and utilization. These results identify an unanticipated mechanism regulating amino acid metabolism in cancer, enabling tumor cells to adapt to changing environmental conditions.

KEYWORDS:

cancer; glioblastoma; glutamate metabolism; glutathione metabolism; mTORC2; xCT

PMID:
28648777
PMCID:
PMC5521991
DOI:
10.1016/j.molcel.2017.05.030
[Indexed for MEDLINE]
Free PMC Article

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