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.

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
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Glutathione
  • Cysteine