PMID- 29555211
OWN - NLM
STAT- MEDLINE
DCOM- 20181211
LR  - 20211204
IS  - 0925-4439 (Print)
IS  - 0925-4439 (Linking)
VI  - 1864
IP  - 6 Pt A
DP  - 2018 Jun
TI  - Inhibition of mTOR complexes protects cancer cells from glutamine starvation 
      induced cell death by restoring Akt stability.
PG  - 2040-2052
LID - S0925-4439(18)30093-0 [pii]
LID - 10.1016/j.bbadis.2018.03.013 [doi]
AB  - Glutamine, a well-established oncometabolite, anaplerotically fuels mitochondrial 
      energy metabolism and modulates activity of mammalian/mechanistic target of 
      rapamycin complexes (mTOR). Currently, mTOR inhibitors are in clinical use for 
      certain types of cancer but with limited success. Since glutamine is essential 
      for growth of many cancers, we reasoned that glutamine deprivation under 
      conditions of mTOR inhibition should be more detrimental to cancer cell survival. 
      However, our results show that when cells are deprived of glutamine concomitant 
      with mTOR inhibition, hepatocarcinoma cells elicit an adaptive response which 
      aids in their survival due to enhanced autophagic flux. Moreover, inhibition of 
      mTOR promotes Akt ubiquitination and its proteasomal degradation however we show 
      that Akt degradation is abrogated by increased autophagy following glutamine 
      withdrawal. Under conditions of glutamine deficiency and mTOR inhibition, the 
      enhanced stability of Akt protein may provide survival cues to cancer cells. 
      Thus, our data uncovers a novel molecular link between glutamine metabolism, 
      autophagy and stability of Akt with cancer cell survival.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Khan, Md Wasim
AU  - Khan MW
AD  - Division of Cell Biology & Physiology, CSIR-Indian Institute of Chemical Biology, 
      Kolkata 700032, India; Department of Medicine, Division of Endocrinology, 
      Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL 60612, 
      USA. Electronic address: mkhan268@uic.edu.
FAU - Layden, Brian T
AU  - Layden BT
AD  - Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, 
      University of Illinois at Chicago, Chicago, IL 60612, USA; Jesse Brown Veterans 
      Affair Medical Center, Chicago, IL, USA.
FAU - Chakrabarti, Partha
AU  - Chakrabarti P
AD  - Division of Cell Biology & Physiology, CSIR-Indian Institute of Chemical Biology, 
      Kolkata 700032, India. Electronic address: pchakrabarti@iicb.res.in.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180317
PL  - Netherlands
TA  - Biochim Biophys Acta Mol Basis Dis
JT  - Biochimica et biophysica acta. Molecular basis of disease
JID - 101731730
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0RH81L854J (Glutamine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Autophagy/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Glutamine/*deficiency
MH  - Humans
MH  - Mice
MH  - NIH 3T3 Cells
MH  - Neoplasms/*drug therapy/pathology
MH  - Protein Kinase Inhibitors/*pharmacology/therapeutic use
MH  - Protein Stability
MH  - Proteolysis/drug effects
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Ubiquitination/drug effects
OTO - NOTNLM
OT  - Akt
OT  - Autophagy
OT  - Cancer metabolism
OT  - Cell survival
OT  - Glutamine
OT  - mTOR
EDAT- 2018/03/21 06:00
MHDA- 2018/12/12 06:00
CRDT- 2018/03/21 06:00
PHST- 2017/11/04 00:00 [received]
PHST- 2018/03/09 00:00 [revised]
PHST- 2018/03/13 00:00 [accepted]
PHST- 2018/03/21 06:00 [pubmed]
PHST- 2018/12/12 06:00 [medline]
PHST- 2018/03/21 06:00 [entrez]
AID - S0925-4439(18)30093-0 [pii]
AID - 10.1016/j.bbadis.2018.03.013 [doi]
PST - ppublish
SO  - Biochim Biophys Acta Mol Basis Dis. 2018 Jun;1864(6 Pt A):2040-2052. doi: 
      10.1016/j.bbadis.2018.03.013. Epub 2018 Mar 17.