Akt/Protein Kinase B Inhibits Cell Death by Preventing the Release of Cytochrome c from Mitochondria

Abstract

Growth factors signaling through the phosphoinositide 3-kinase/Akt pathway promote cell survival. The mechanism by which the serine/threonine kinase Akt prevents cell death remains unclear. We have previously shown that Akt inhibits the activity of DEVD-targeted caspases without changing the steady-state levels of Bcl-2 and Bcl-x L . Here we show that Akt inhibits apoptosis and the processing of procaspases to their active forms by delaying mitochondrial changes in a caspase-independent manner. Akt activation is sufficient to inhibit the release of cytochrome c from mitochondria and the alterations in the inner mitochondrial membrane potential. However, Akt cannot inhibit apoptosis induced by microinjection of cytochrome c. We also demonstrated that Akt inhibits apoptosis and cytochrome c release induced by several proapoptotic Bcl-2 family members. Taken together, our results show that Akt promotes cell survival by intervening in the apoptosis cascade before cytochrome c release and caspase activation via a mechanism that is distinct from Bad phosphorylation.

Apoptosis to necrosis switching downstream of apoptosome formation requires inhibition of both glycolysis and oxidative phosphorylation in a BCL-XL- and PKB/AKT-independent fashion

“…In fact, it enhances glucose uptake by stimulating the expression of the plasma membrane glucose transporter Glut-1, 18 and it mediates the activation of 6-phosphofructo-2-kinase 19 and hexokinase. 20 Thus, PKB/Akt activation may favor cell survival, 21,22 or alternatively it may support execution of the final apoptotic steps in committed cells. We have observed that PKB/Akt activity is inhibited by ddFSK, but a constitutive active form of the enzyme cannot counteract any of the inhibitory effects of the drug on cell energy metabolism.…”

“…21 The hallmark of PKB/ Akt activation is the phosphorylation at the Thr308/Ser473 residues. As reported in Figure 10a, the phosphorylation of Ser473-Akt was abolished by ddFSK treatment independently of apoptosis induction.…”

“…[15][16][17] The PKB/Akt serine/threonine kinase increases glucose uptake and glycolytic activity, [18][19][20] and thus stimulates cell metabolism by enhancing substrate availability for mitochondrial activity. 21,22 In this study, we provide evidence that treatment of Tlymphoma cells and other cell models with several intrinsic apoptotic agents results in a PCD program aborted downstream of apoptosome formation when cells are exposed to 1,9-dideoxyforskolin (ddFSK), a diterpenoid often used as a negative control of the adenylyl cyclase activator forskolin. On the contrary, the response mediated by death receptor engagement is not affected or slightly increased by ddFSK.…”

Differential radiosensitisation by ZD1839 (Iressa), a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines

“…This inhibition of phosphorylation of serine residues also inhibits the interaction between BAD and BCL-XL, an antiapoptotic regulatory protein of the BH3 subfamily, resulting in BAD remaining in an active proapoptotic form. Reports have also suggested that ZD1839 decreases the phosphorylation of Akt via the phosphatidylinositol 3-kinase pathway resulting in decreased phosphorylation of BAD again resulting in an increase in the proportion of the active form of this regulatory protein (Kennedy et al, 1999). A combination of the proposed models or elements of the models may result in the loss of the fine balance of the EGFR signalling cascade, which protects against radiation-induced cell damage, thereby leading to increased cell death.…”

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

“…Another survival pathway that protects mitochondrial integrity is the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway (Kennedy et al, 1999). To see if Akt signaling is affected, we tested how ARC may modulate this pathway in NB-1691 cells.…”