Akt-Dependent Glucose Metabolism Promotes Mcl-1 Synthesis to Maintain Cell Survival and Resistance to Bcl-2 Inhibition

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-08, Vol.71 (15), p.5204-5213
• Main Authors: COLOFF, Jonathan L, MACINTYRE, Andrew N, NICHOLS, Amanda G, TINGYU LIU, GALLO, Catherine A, PLAS, David R, RATHMELL, Jeffrey C
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - physiology; Adenosine Triphosphate - metabolism; Animals; Antineoplastic agents; Apoptosis; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Biological and medical sciences; Biphenyl Compounds - pharmacology; Cell Line, Tumor - drug effects; Cell Survival; Gene Expression Regulation, Neoplastic - drug effects; Glucose - metabolism; Glycolysis - drug effects; Humans; Jurkat Cells - drug effects; Lymphoma, Large B-Cell, Diffuse - pathology; Mechanistic Target of Rapamycin Complex 1; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Mice; Multiprotein Complexes; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - physiology; Nitrophenols - pharmacology; Pharmacology. Drug treatments; Phosphoproteins - physiology; Piperazines - pharmacology; Proteins - antagonists & inhibitors; Proteins - physiology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - physiology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - physiology; Ribosomal Protein S6 Kinases - physiology; Sulfonamides - pharmacology; T-Lymphocytes - drug effects; TOR Serine-Threonine Kinases; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-4531

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.