PMID- 25798620
OWN - NLM
STAT- MEDLINE
DCOM- 20150702
LR  - 20220318
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 125
IP  - 4
DP  - 2015 Apr
TI  - Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR 
      inhibitor treatment.
PG  - 1591-602
LID - 78239 [pii]
LID - 10.1172/JCI78239 [doi]
AB  - The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of 
      cancer, rendering it a compelling drug target; however, the impact of mTOR 
      inhibition on metabolic reprogramming in cancer is incompletely understood. Here, 
      by integrating metabolic and functional studies in glioblastoma multiforme (GBM) 
      cell lines, preclinical models, and clinical samples, we demonstrate that the 
      compensatory upregulation of glutamine metabolism promotes resistance to mTOR 
      kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase 
      (GLS) and glutamate levels are elevated following mTOR kinase inhibitor 
      treatment. Moreover, these mTOR inhibitor-dependent metabolic alterations were 
      confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor 
      treatment promoted GBM survival in an alpha-ketoglutarate-dependent (alphaKG-dependent) 
      manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS 
      resulted in massive synergistic tumor cell death and growth inhibition in 
      tumor-bearing mice. These results highlight a critical role for compensatory 
      glutamine metabolism in promoting mTOR inhibitor resistance and suggest that 
      rational combination therapy has the potential to suppress resistance.
FAU - Tanaka, Kazuhiro
AU  - Tanaka K
FAU - Sasayama, Takashi
AU  - Sasayama T
FAU - Irino, Yasuhiro
AU  - Irino Y
FAU - Takata, Kumi
AU  - Takata K
FAU - Nagashima, Hiroaki
AU  - Nagashima H
FAU - Satoh, Naoko
AU  - Satoh N
FAU - Kyotani, Katsusuke
AU  - Kyotani K
FAU - Mizowaki, Takashi
AU  - Mizowaki T
FAU - Imahori, Taichiro
AU  - Imahori T
FAU - Ejima, Yasuo
AU  - Ejima Y
FAU - Masui, Kenta
AU  - Masui K
FAU - Gini, Beatrice
AU  - Gini B
FAU - Yang, Huijun
AU  - Yang H
FAU - Hosoda, Kohkichi
AU  - Hosoda K
FAU - Sasaki, Ryohei
AU  - Sasaki R
FAU - Mischel, Paul S
AU  - Mischel PS
FAU - Kohmura, Eiji
AU  - Kohmura E
LA  - eng
GR  - R01 NS073831/NS/NINDS NIH HHS/United States
GR  - U54 CA151819/CA/NCI NIH HHS/United States
GR  - CA151819/CA/NCI NIH HHS/United States
GR  - NS73831/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150323
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Benzophenanthridines)
RN  - 0 (Indoles)
RN  - 0 (Ketoglutaric Acids)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Purines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (compound 968)
RN  - 0RH81L854J (Glutamine)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.5.1.2 (Glutaminase)
RN  - H5669VNZ7V (PP242)
SB  - IM
MH  - Aged
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Benzophenanthridines/administration & dosage/pharmacology/*therapeutic use
MH  - Brain Neoplasms/*drug therapy/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Citric Acid Cycle
MH  - Drug Resistance, Neoplasm/*physiology
MH  - Drug Synergism
MH  - Energy Metabolism
MH  - Gas Chromatography-Mass Spectrometry
MH  - Glioblastoma/*drug therapy/metabolism/pathology
MH  - Glutamic Acid/metabolism
MH  - Glutaminase/antagonists & inhibitors/biosynthesis/genetics/*physiology
MH  - Glutamine/*metabolism
MH  - Glycolysis
MH  - Humans
MH  - Indoles/administration & dosage/*pharmacology/therapeutic use
MH  - Ketoglutaric Acids/metabolism
MH  - Magnetic Resonance Spectroscopy
MH  - Male
MH  - Metabolome/drug effects
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - *Molecular Targeted Therapy
MH  - Neoplasm Proteins/antagonists & inhibitors/biosynthesis/genetics/*physiology
MH  - Protein Kinase Inhibitors/*pharmacology/therapeutic use
MH  - Purines/administration & dosage/*pharmacology/therapeutic use
MH  - RNA, Small Interfering/pharmacology
MH  - Rotarod Performance Test
MH  - Signal Transduction/drug effects/physiology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Temporal Lobe/metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC4396477
EDAT- 2015/03/24 06:00
MHDA- 2015/07/03 06:00
PMCR- 2015/07/01
CRDT- 2015/03/24 06:00
PHST- 2014/07/28 00:00 [received]
PHST- 2015/02/05 00:00 [accepted]
PHST- 2015/03/24 06:00 [entrez]
PHST- 2015/03/24 06:00 [pubmed]
PHST- 2015/07/03 06:00 [medline]
PHST- 2015/07/01 00:00 [pmc-release]
AID - 78239 [pii]
AID - 10.1172/JCI78239 [doi]
PST - ppublish
SO  - J Clin Invest. 2015 Apr;125(4):1591-602. doi: 10.1172/JCI78239. Epub 2015 Mar 23.