Authors:
Jonathan L. Coloff, Yuxing Zhao, Jessica A. Wofford, Jeffrey C. Rathmell
Summary:
Akt is a serine/threonine kinase that plays important roles in the regulation of both cell death and glucose metabolism. The PI3K/Akt pathway is activated in many cancers, and both of these qualities of Akt are thought to contribute to its oncogenecity, as many cancer cells demonstrate a highly glycolytic phenotype known as the Warburg Effect and are resistant to growth factor withdrawal-induced apoptotic cell death. However, when glucose becomes limiting, Akt is no longer able to exert its anti-apoptotic effects. The mechanism for which active Akt-expressing cells require glucose to prevent cell death remains poorly understood, with evidence suggesting that Akt utilizes glucose to regulate cell death independent of Bcl-2 family proteins. Here we utilize a cytokine-dependent cell line to present evidence that Akt promotes glucose metabolism to regulate Bcl-2 family proteins which are critical for Akt to maintain cell survival. Normally, cytokine withdrawal leads to loss of glucose uptake and metabolism, degradation of the anti-apoptotic Bcl-2 family member Mcl-1, induction of the pro-apoptotic BH3-only protein Puma, and apoptotic cell death. Expression of an oncogenic form of Akt, myrAkt, is able to maintain glucose uptake and metabolism, prevent the loss of Mcl-1, inhibit the induction of Puma, and prevent cell death in cells withdrawn from cytokine. When glucose is limiting, however, Akt is no longer able to maintain Mcl-1 or prevent Puma induction, suggesting that Akt’s ability to regulate these Bcl-2 family members is dependent on its ability to maintain glucose uptake and metabolism. The importance of Akt’s glucose-mediated regulation of Mcl-1 is demonstrated by findings that Akt can no longer maintain survival upon cytokine withdrawal when Mcl-1 is knocked-down by RNAi. Conversely, glucose-withdrawal induced cell death in myrAkt expressing cells is inhibited when Puma induction is prevented by RNAi. Together, these experiments suggest that Akt’s dependence on glucose to prevent cell death is at least partially required in order regulate the Bcl-2 family members Mcl-1 and Puma. Akt’s dependence on glucose to provide an anti-apoptotic signal may indicate a metabolic addiction to glucose, similar to described oncogene addictions, and may provide a novel avenue for metabolic treatments in cancer.
Source:
American Association for Cancer Research (AACR); (04/15/08)