Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase.

By Kathrin Gottlob, Nathan D. Majewski, S. Kennedy, E. Kandel, R. Robey, N. Hay. Genes & Development, 2001

978 citations recorded by the source corpus.

The serine/threonine kinase Akt/PKB is a major downstream effector of growth factor-mediated cell survival. Activated Akt, like Bcl-2 and Bcl-xL, prevents closure of a PT pore component, the voltage-dependent anion channel (VDAC); intracellular acidification; mitochondrial hyperpolarization; and the decline in oxidative phosphorylation that precedes cytochrome c release. However, unlike Bcl-2 and Bcl-xL, the ability of activated Akt to preserve mitochondrial integrity, and thereby inhibit apoptosis, requires glucose availability and is coupled to its metabolism. Hexokinases are known to bind to VDAC and directly couple intramitochondrial ATP synthesis to glucose metabolism. We provide evidence that such coupling serves as a downstream effector function for Akt. First, Akt increases mitochondria-associated hexokinase activity. Second, the antiapoptotic activity of Akt requires only the first committed step of glucose metabolism catalyzed by hexokinase. Finally, ectopic hexokinase expression mimics the ability of Akt to inhibit cytochrome c release and apoptosis. We therefore propose that Akt increases coupling of glucose metabolism to oxidative phosphorylation and regulates PT pore opening via the promotion of hexokinase-VDAC interaction at the outer mitochondrial membrane.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/db9593d26300618f370871e3a4b71b24fd28840c

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Citations in the corpus

Caspases in apoptosis and beyond (2008, background): “For example, cell survival mediated by the oncogene, Akt, is dependent on glucose metabolism to inhibit Bax activation and cytochrome c release (Gottlob et al., 2001; Rathmell et al., 2003).”
Hypoxia-Inducible Factor 1 and Dysregulated c-Myc Cooperatively Induce Vascular Endothelial Growth Factor and Metabolic Switches Hexokinase 2 and Pyruvate Dehydrogenase Kinase 1 (2007, background): “Particularly, in addition to its rate-limiting role in glucose metabolism, HK2 is overexpressed in most human cancers and suppresses proapoptotic molecules including Bad and Bax at the mitochondrial outer membrane, by which HK2 functions as a key coordinator by integrating glucose metabolism with ap”
Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer (2008, background): “The molecular characteristics of histologically identical cancers are often dissimilar and molecular heterogeneity frequently exists within a single tumour.”
Mitochondrial mutations in cancer (2006, background): “The binding of hexokinase II to VDAC also stabilizes the mtPTP and inhibits induction of apoptosis (Pedersen et al., 2002; Gatenby and Gillies, 2004) by antagonizing the pro-apoptotic action of Bax and Bak (Gottlob et al., 2001; Birnbaum, 2004; Majewski et al., 2004a, b).”
PI3K/Akt: getting it right matters (2008, background): “In addition, Akt activation has been shown to cause the translocation of hexokinase to the mitochondria for the purpose of eliciting the capture of intracellular glucose by phosphorylation (Gottlob et al., 2001).”
Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. (2007, background): “…Heilig et al., 2003), immune responses fail as lymphocytes undergo apoptosis or produce inappropriate cytokines (Rathmell et al., 2000; Krauss et al., 2001; Cham and Gajewski, 2005), and cancer cells show enhanced apoptosis (Gottlob et al., 2001; Plas et al., 2001; Kansara and Berridge, 2004).”
Akt Stimulates Aerobic Glycolysis in Cancer Cells (2004, background): “Additionally, Akt has been shown to maintain mitochondrial membrane potential and hexokinase activity of nontransformed cells under apoptogenic conditions (13, 14).”
Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme (2011, background): “…of lactate Previous studies have demonstrated that growth factor stimu lation, resulting in activation of the PI3K–AKT pathway, promotes translocation of HK2 to the outer mitochondrial membrane, resulting in increased protein stability (Bustamante and Pedersen, 1977; Gottlob et al., 2001).”
Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. (2006, background): “Other reports demonstrated a glucose-dependent AKT-mediated protection and showed that hexokinase activity confers protection downstream of AKT (Gottlob et al., 2001).”
Akt-Directed Glucose Metabolism Can Prevent Bax Conformation Change and Promote Growth Factor-Independent Survival (2003, background): “Because Akt has been reported to maintain mitochondrial hexokinase activity and HK1 overexpression can support short-term viability upon apoptotic stimuli (8, 20), FL5.”
Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. (2011, positive): “Akt activation enhances flux through glycolysis (Elstrom et al 2004) in part by maintaining hexokinase association with mitochondria (Gottlob et al 2001) and activating phosphofructokinase 2 (PFK-2) through phosphorylation (Deprez et al 1997).”