The protein kinase Akt is involved in various cellular processes, including cell proliferation, growth and metabolism. Hyperactivation of Akt is commonly observed in human tumours and so this pathway has been the focus of targeted drug discovery. However, Akt also plays an essential role in other physiological processes, such as the insulin-regulated transport of glucose into muscle and fat cells. This process, which is essential for whole-body glucose homoeostasis in mammals, is thought to be mediated via Akt-dependent movement of GLUT4 glucose transporters to the plasma membrane. In the present study, we have investigated the metabolic side effects of non-ATP-competitive allosteric Akt inhibitors. In 3T3-L1 adipocytes, these inhibitors caused a decrease in the Akt signalling pathway concomitant with reduced glucose uptake. Surprisingly, a similar reduction in GLUT4 translocation to the plasma membrane was not observed. Further investigation revealed that the inhibitory effects of these compounds on glucose uptake in 3T3-L1 adipocytes were independent of the Akt signalling pathway. The inhibitors also inhibited glucose transport into other cell types, including human erythrocytes and T-47D breast cancer cells, suggesting that these effects are not specific to GLUT4. We conclude that these drugs may, at least in part, inhibit tumorigenesis through inhibition of tumour cell glucose transport.
Research Article| October 25 2010
Akt inhibitors reduce glucose uptake independently of their effects on Akt
David E. James
David E. James 2
*Diabetes and Obesity Research Program, The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
†School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2050, Australia
2To whom correspondence should be addressed (email firstname.lastname@example.org).
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Shi-Xiong Tan, Yvonne Ng, David E. James; Akt inhibitors reduce glucose uptake independently of their effects on Akt. Biochem J 15 November 2010; 432 (1): 191–198. doi: https://doi.org/10.1042/BJ20100750
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