PMID- 28648777
OWN - NLM
STAT- MEDLINE
DCOM- 20170926
LR  - 20211204
IS  - 1097-4164 (Electronic)
IS  - 1097-2765 (Print)
IS  - 1097-2765 (Linking)
VI  - 67
IP  - 1
DP  - 2017 Jul 6
TI  - mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the 
      Cystine-Glutamate Antiporter xCT.
PG  - 128-138.e7
LID - S1097-2765(17)30394-5 [pii]
LID - 10.1016/j.molcel.2017.05.030 [doi]
AB  - 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.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Gu, Yuchao
AU  - Gu Y
AD  - 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.
FAU - Albuquerque, Claudio P
AU  - Albuquerque CP
AD  - Ludwig Institute for Cancer Research, University of California, San Diego, La 
      Jolla, CA 92093, USA.
FAU - Braas, Daniel
AU  - Braas D
AD  - 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.
FAU - Zhang, Wei
AU  - Zhang W
AD  - Department of Medicine, UCSD School of Medicine, La Jolla, CA 92093, USA.
FAU - Villa, Genaro R
AU  - Villa GR
AD  - 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.
FAU - Bi, Junfeng
AU  - Bi J
AD  - Ludwig Institute for Cancer Research, University of California, San Diego, La 
      Jolla, CA 92093, USA.
FAU - Ikegami, Shiro
AU  - Ikegami S
AD  - Division of Neurological Surgery, Chiba Cancer Center, Chiba 260-8717, Japan.
FAU - Masui, Kenta
AU  - Masui K
AD  - Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
FAU - Gini, Beatrice
AU  - Gini B
AD  - Department of Medicine, University of California, San Francisco, San Francisco, 
      CA 94143, USA.
FAU - Yang, Huijun
AU  - Yang H
AD  - Ludwig Institute for Cancer Research, University of California, San Diego, La 
      Jolla, CA 92093, USA.
FAU - Gahman, Timothy C
AU  - Gahman TC
AD  - Small Molecule Discovery Program, Ludwig Institute for Cancer Research, 
      University of California, San Diego, La Jolla, CA 92093, USA.
FAU - Shiau, Andrew K
AU  - Shiau AK
AD  - Small Molecule Discovery Program, Ludwig Institute for Cancer Research, 
      University of California, San Diego, La Jolla, CA 92093, USA.
FAU - Cloughesy, Timothy F
AU  - Cloughesy TF
AD  - Department of Neurology, David Geffen School of Medicine, University of 
      California, Los Angeles, Los Angeles, CA 90095, USA.
FAU - Christofk, Heather R
AU  - Christofk HR
AD  - 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.
FAU - Zhou, Huilin
AU  - Zhou H
AD  - 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.
FAU - Guan, Kun-Liang
AU  - Guan KL
AD  - Department of Pharmacology, UCSD School of Medicine, La Jolla, CA 92093, USA; 
      Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093 USA.
FAU - Mischel, Paul S
AU  - Mischel PS
AD  - 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.
LA  - eng
GR  - R01 NS073831/NS/NINDS NIH HHS/United States
GR  - R35 CA196878/CA/NCI NIH HHS/United States
GR  - R01 GM051586/GM/NIGMS NIH HHS/United States
GR  - R01 GM116897/GM/NIGMS NIH HHS/United States
GR  - F31 CA186668/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20170622
PL  - United States
TA  - Mol Cell
JT  - Molecular cell
JID - 9802571
RN  - 0 (Amino Acid Transport System y+)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (SLC7A11 protein, human)
RN  - 0RH81L854J (Glutamine)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - GAN16C9B8O (Glutathione)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - A549 Cells
MH  - Amino Acid Transport System y+/genetics/*metabolism
MH  - Brain Neoplasms/*enzymology/genetics/pathology
MH  - Cysteine/*metabolism
MH  - Glioblastoma/*enzymology/genetics/pathology
MH  - Glutamine/*metabolism
MH  - Glutathione/biosynthesis
MH  - HEK293 Cells
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Multiprotein Complexes/genetics/*metabolism
MH  - Mutation
MH  - Phosphorylation
MH  - Protein Binding
MH  - Proteomics/methods
MH  - RNA Interference
MH  - Serine
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Tandem Mass Spectrometry
MH  - Time Factors
MH  - Transfection
MH  - Tumor Microenvironment
PMC - PMC5521991
MID - NIHMS880701
OTO - NOTNLM
OT  - cancer
OT  - glioblastoma
OT  - glutamate metabolism
OT  - glutathione metabolism
OT  - mTORC2
OT  - xCT
EDAT- 2017/06/27 06:00
MHDA- 2017/09/28 06:00
PMCR- 2018/07/06
CRDT- 2017/06/27 06:00
PHST- 2016/12/09 00:00 [received]
PHST- 2017/04/21 00:00 [revised]
PHST- 2017/05/26 00:00 [accepted]
PHST- 2017/06/27 06:00 [pubmed]
PHST- 2017/09/28 06:00 [medline]
PHST- 2017/06/27 06:00 [entrez]
PHST- 2018/07/06 00:00 [pmc-release]
AID - S1097-2765(17)30394-5 [pii]
AID - 10.1016/j.molcel.2017.05.030 [doi]
PST - ppublish
SO  - Mol Cell. 2017 Jul 6;67(1):128-138.e7. doi: 10.1016/j.molcel.2017.05.030. Epub 
      2017 Jun 22.