Document Detail

Akt-dependent glucose metabolism promotes Mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition.
MedLine Citation:
PMID:  21670080     Owner:  NLM     Status:  MEDLINE    
Most cancer cells utilize aerobic glycolysis, and activation of the phosphoinositide 3-kinase/Akt/mTOR pathway can promote this metabolic program to render cells glucose dependent. Although manipulation of glucose metabolism may provide a means to specifically eliminate cancer cells, mechanistic links between cell metabolism and apoptosis remain poorly understood. Here, we examined the role and metabolic regulation of the antiapoptotic Bcl-2 family protein Mcl-1 in cell death upon inhibition of Akt-induced aerobic glycolysis. In the presence of adequate glucose, activated Akt prevented the loss of Mcl-1 expression and protected cells from growth factor deprivation-induced apoptosis. Mcl-1 associated with and inhibited the proapoptotic Bcl-2 family protein Bim, contributing to cell survival. However, suppression of glucose metabolism led to induction of Bim, decreased expression of Mcl-1, and apoptosis. The proapoptotic Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, shows clinical promise, but Mcl-1 upregulation can promote resistance. Importantly, inhibition of glucose metabolism or mTORC1 overcame Mcl-1-mediated resistance in diffuse large B cell leukemic cells. Together these data show that Mcl-1 protein synthesis is tightly controlled by metabolism and that manipulation of glucose metabolism may provide a mechanism to suppress Mcl-1 expression and sensitize cancer cells to apoptosis.
Jonathan L Coloff; Andrew N Macintyre; Amanda G Nichols; Tingyu Liu; Catherine A Gallo; David R Plas; Jeffrey C Rathmell
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-06-13
Journal Detail:
Title:  Cancer research     Volume:  71     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-01     Completed Date:  2011-10-03     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5204-13     Citation Subset:  IM    
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MeSH Terms
Adaptor Proteins, Signal Transducing / physiology
Adenosine Triphosphate / metabolism
Apoptosis Regulatory Proteins / antagonists & inhibitors*,  metabolism
Biphenyl Compounds / pharmacology
Cell Line, Tumor / drug effects
Cell Survival
Gene Expression Regulation, Neoplastic / drug effects
Glucose / metabolism*
Glycolysis / drug effects
Jurkat Cells / drug effects
Lymphoma, Large B-Cell, Diffuse / pathology
Membrane Proteins / antagonists & inhibitors*,  metabolism
Multiprotein Complexes
Myeloid Cell Leukemia Sequence 1 Protein
Neoplasm Proteins / physiology*
Nitrophenols / pharmacology
Phosphoproteins / physiology
Piperazines / pharmacology
Proteins / antagonists & inhibitors,  physiology
Proto-Oncogene Proteins / antagonists & inhibitors*,  metabolism
Proto-Oncogene Proteins c-akt / physiology*
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors,  biosynthesis*,  genetics,  physiology
Ribosomal Protein S6 Kinases / physiology
Sulfonamides / pharmacology
T-Lymphocytes / drug effects
TOR Serine-Threonine Kinases
Grant Support
AI063345/AI/NIAID NIH HHS; CA123350/CA/NCI NIH HHS; CA133164/CA/NCI NIH HHS; R01 AI063345/AI/NIAID NIH HHS; R01 AI063345-05/AI/NIAID NIH HHS; R01 CA123350/CA/NCI NIH HHS; R01 CA123350-05/CA/NCI NIH HHS; R01 CA133164/CA/NCI NIH HHS; R01 CA133164-04/CA/NCI NIH HHS
Reg. No./Substance:
0/ABT-737; 0/Adaptor Proteins, Signal Transducing; 0/Apoptosis Regulatory Proteins; 0/Bcl-2-like protein 11; 0/Biphenyl Compounds; 0/EIF4EBP1 protein, human; 0/Mcl1 protein, mouse; 0/Membrane Proteins; 0/Multiprotein Complexes; 0/Myeloid Cell Leukemia Sequence 1 Protein; 0/Neoplasm Proteins; 0/Nitrophenols; 0/Phosphoproteins; 0/Piperazines; 0/Proteins; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Sulfonamides; 0/mechanistic target of rapamycin complex 1; 8L70Q75FXE/Adenosine Triphosphate; EC Serine-Threonine Kinases; EC protein, human; EC Proteins c-akt; EC Protein S6 Kinases; IY9XDZ35W2/Glucose

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