Is Akt the “Warburg kinase”?—Akt-energy metabolism interactions and oncogenesis
The serine/threonine kinase Akt – also known as protein kinase B (PKB) – has emerged as one of the most frequently activated protein kinases in human cancer. In fact, most, if not all, tumors ultimately find a way to activate this important kinase. As such, Akt activation constitutes a hallmark of most cancer cells, and such ubiquity presumably connotes important roles in tumor genesis and/or progression. Likewise, the hypermetabolic nature of cancer cells and their increased reliance on “aerobic glycolysis”, as originally described by Otto Warburg and colleagues, are considered metabolic hallmarks of cancer cells. In this review, we address the specific contributions of Akt activation to the signature metabolic features of cancer cells, including the so-called “Warburg effect”.
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Fig. 1. Coupling between Akt-mediated cellular energy metabolism, cell survival and proliferation. Following activation by PI3K, PDK1, and mTORC2, Akt increases cellular ATP production by accelerating both glycolytic and oxidative metabolism. Akt may increase oxidative phosphorylation by enhancing metabolic coupling between glycolysis and oxidative phosphorylation through facilitation of mitochondrial hexokinase (mtHK; i.e. HKI and HKII) association with VDAC and mitochondria, and by as yet unknown mechanisms. By facilitating mtHK association with mitochondria, Akt increases cell survival. Akt also enhances glycolytic flux by multiple mechanisms. First, it increases glucose (Glc) uptake by increasing the expression of Glc transporters (GLUT1, GLUT2, and GLUT4), and, in some cases, by promoting translocation to the plasma membrane. Second, enhanced coupling between oxidative phosphorylation and glycolysis may also kinetically favor enhanced glycolytic flux. Third, hyperactive Akt activates mTORC1, which promotes HIF1α accumulation under normoxic conditions and increases GLUT1, HKII, and lactate dehydrogenase (LDH) abundance. The increased capacity for both Glc transport and phosphorylation results in increased glucose-6-phosphate (Glc-6-P) availability for utilization in both glycolysis and the pentose phosphate pathway (PPP). Fourth, Akt phosphorylates and activates phosphofructokinase-2 (PFK2), which leads to allosteric activation of phosphofructokinase-1 (PFK1) by the PFK2 product fructose-2,6-bisphosphate (Fru-2,6-P2). Citrate generated in the mitochondrial TCA cycle is exported to the cytoplasm, where it is utilized for acetyl-coA generation by ATP-citrate lyase (ACL), which is directly phosphorylated and activated by Akt. By increasing citrate utilization, Akt may help drive TCA cycle flux, in addition to providing precursors for lipid biosynthesis for new membrane generation. Finally, Akt-increased cellular ATP levels serve to maintain low AMPK activity, which is required for full mTORC1 activation. As the most critical downstream effector of Akt, mTORC1 is largely responsible for the contributions of Akt to cell growth, cell proliferation, and susceptibility to oncogenic transformation