Akt-Directed Glucose Metabolism Can Prevent Bax Conformation Change and Promote Growth Factor-Independent Survival

Abstract

The serine/threonine kinase Akt is a component of many receptor signal transduction pathways and can prevent cell death following growth factor withdrawal. Here, we show that Akt inhibition of cell death is not dependent on new protein translation. Instead, Akt inhibition of cell death requires glucose hydrolysis through glycolysis. Akt was found to regulate multiple steps in glycolysis via posttranscriptional mechanisms that included localization of the glucose transporter, Glut1, to the cell surface and maintenance of hexokinase function in the absence of extrinsic factors. To test the role of glucose uptake and phosphorylation in growth factor-independent survival, cells were transfected with Glut1 and hexokinase 1 (Glut1/HK1) cells. Glut1/HK1 cells accumulated Glut1 on the cell surface and had high glucose uptake capacity similar to that of cells with constitutively active Akt (mAkt). Unlike mAkt-expressing cells, however, they did not consume more glucose, did not maintain prolonged phosphofructokinase-1 protein levels and activity, and did not maintain pentose phosphate shuttle activity in the absence of growth factor. Nevertheless, expression of Glut1 and HK1 promoted increased cytosolic NADH and NADPH levels relative to those of the control cells upon growth factor withdrawal, prevented activation of Bax, and promoted growth factor-independent survival. These data indicate that Bax conformation is sensitive to glucose metabolism and that maintaining glucose uptake and phosphorylation can promote cell survival in the absence of growth factor. Furthermore, Akt required glucose and the ability to perform glycolysis to prevent Bax activation. The prevention of Bax activation by posttranscriptional regulation of glucose metabolism may, therefore, be a required aspect of the ability of Akt to maintain long-term cell survival in the absence of growth factors.

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

“…These increases were less but of the same order of magnitude as those reported for MyrAkt. 35 Whereas mitochondrial HK activity appears to be independent of IL-3 in T cells expressing MyrAkt, 42 CSF-1 treatment had an additional and substantial effect, consistent with the finding that CSF-1 further stimulated Akt activity in DKI/p110* and DKI/E40K cells ( Figure 3e). …”

“…Previous studies showed that enforced overexpression of MyrAkt in B cells was completely protective against cell death induced by IL-3 withdrawl and that this was dependent on glucose availability. 42 When a signaling pathway is dysregulated, such as from chronic Akt activation owing to MyrAkt overexpression, cells can become addicted to the growth/ survival effects conferred by the pathway and exhibit hypersensitivity to inhibition of that pathway. Our results extend the observations made with MyrAkt to more physiologic situations such as the DKI receptor where growth factor signaling and feedback mechanisms remain largely intact.…”

Sugar-free approaches to cancer cell killing

“…A few examples are cited as follows: oncogenic Ras or activation of the PI3K/Akt pathway promotes glycolysis. Akt stimulates membrane localization of glucose transporters and enhances transcription or activity of glycolytic enzymes such as hexokinase and phosphofructokinase (Gottlob et al, 2001;Rathmell et al, 2003). K-Ras promotes transcription of several glycolytic enzymes (Chiaradonna et al, 2006).…”

“…They demonstrated that by increasing glucose uptake through Glut1 overexpression in hematopoietic cells, they could efficiently delay apoptosis induced by interleukin-3 withdrawal. In addition, it was shown that glucose uptake and phosphorylation are required by constitutively active Akt to protect from interleukin-3 withdrawal (Rathmell et al, 2003). The process of deciphering the mechanism behind it has begun.…”

Transcription factor ATF3 mediates the radioresistance of breast cancer

“…Multiple biological processes, such as cell proliferation, cell metabolism and cell survival, are all regulated by Akt 10. The PI3K/Akt signal pathway mediates cell survival by promoting aerobic glycolysis 11. Most of the cancer cells produce abundant lactate to supply energy, but it is inefficient to generate ATP.…”