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

Yuchao Gu; Claudio P Albuquerque; Daniel Braas; Wei Zhang; Genaro R Villa; Junfeng Bi; Shiro Ikegami; Kenta Masui; Beatrice Gini; Huijun Yang; Timothy C Gahman; Andrew K Shiau; Timothy F Cloughesy; Heather R Christofk; Huilin Zhou; Kun-Liang Guan; Paul S Mischel

doi:10.1016/j.molcel.2017.05.030

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

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

Authors

Yuchao Gu¹, Claudio P Albuquerque², Daniel Braas³, Wei Zhang⁴, Genaro R Villa⁵, Junfeng Bi², Shiro Ikegami⁶, Kenta Masui⁷, Beatrice Gini⁸, Huijun Yang², Timothy C Gahman⁹, Andrew K Shiau⁹, Timothy F Cloughesy¹⁰, Heather R Christofk³, Huilin Zhou¹¹, Kun-Liang Guan¹², Paul S Mischel¹³

Affiliations

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: [email protected].

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.

MeSH terms

A549 Cells
Amino Acid Transport System y+ / genetics
Amino Acid Transport System y+ / metabolism*
Brain Neoplasms / enzymology*
Brain Neoplasms / genetics
Brain Neoplasms / pathology
Cysteine / metabolism*
Glioblastoma / enzymology*
Glioblastoma / genetics
Glioblastoma / pathology
Glutamine / metabolism*
Glutathione / biosynthesis
HEK293 Cells
Humans
Mechanistic Target of Rapamycin Complex 1
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism*
Mutation
Phosphorylation
Protein Binding
Proteomics / methods
RNA Interference
Serine
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism*
Tandem Mass Spectrometry
Time Factors
Transfection
Tumor Microenvironment

Substances

Amino Acid Transport System y+
Multiprotein Complexes
SLC7A11 protein, human
Glutamine
Serine
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
Glutathione
Cysteine

Abstract

MeSH terms

Substances

Grants and funding