Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / physiology
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Adenosine Triphosphate / metabolism
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Animals
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Apoptosis
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Apoptosis Regulatory Proteins / antagonists & inhibitors*
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Biphenyl Compounds / pharmacology
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Cell Cycle Proteins
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Cell Line, Tumor / drug effects
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Cell Survival
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Gene Expression Regulation, Neoplastic / drug effects
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Glucose / metabolism*
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Glycolysis / drug effects
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Humans
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Jurkat Cells / drug effects
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Lymphoma, Large B-Cell, Diffuse / pathology
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Mechanistic Target of Rapamycin Complex 1
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / metabolism
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Mice
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Multiprotein Complexes
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / physiology*
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Nitrophenols / pharmacology
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Phosphoproteins / physiology
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Piperazines / pharmacology
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Proteins / antagonists & inhibitors
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Proteins / physiology
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt / physiology*
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / physiology
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Ribosomal Protein S6 Kinases / physiology
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Sulfonamides / pharmacology
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T-Lymphocytes / drug effects
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TOR Serine-Threonine Kinases
Substances
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ABT-737
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Biphenyl Compounds
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Mcl1 protein, mouse
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Membrane Proteins
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Multiprotein Complexes
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Nitrophenols
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Phosphoproteins
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Piperazines
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides
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Adenosine Triphosphate
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AKT1 protein, human
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases
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TOR Serine-Threonine Kinases
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Glucose