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Review
, 31 (5), 492-5

Switching Akt: From Survival Signaling to Deadly Response

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Review

Switching Akt: From Survival Signaling to Deadly Response

Marek Los et al. Bioessays.

Abstract

Akt, a protein kinase hyperactivated in many tumors, plays a major role in both cell survival and resistance to tumor therapy. A recent study,1 along with other evidences, shows interestingly, that Akt is not a single-function kinase, but may facilitate rather than inhibit cell death under certain conditions. This hitherto undetected function of Akt is accomplished by its ability to increase reactive oxygen species and to suppress antioxidant enzymes. The ability of Akt to down-regulate antioxidant defenses uncovers a novel Achilles' heel, which could be exploited by oxidant therapies in order to selectively eradicate tumor cells that express high levels of Akt activity.

Figures

Figure 1
Figure 1
Simplified scheme of the double-edged role of Akt in tumor development. Moderate or unsustained levels of Akt activity inhibit apoptosis and promote cell growth and angiogenesis through various downstream effectors. Inhibition of caspase-9 and the Bcl-2 protein Bad, or activation of MDM2 and NF-κB prevent apoptosis. In addition, stimulation of amino acid and glucose transporters (Glut), or inhibition of GSK3 and tuberous sclerosis complex-2 (TSC2), along with the modulation of other not-indicated enzymes, exert growth-promoting effects by activating the mTOR pathway and oxidative metabolism. Akt can stimulate angiogenesis by activating endothelial nitric oxide synthase (eNOS) and HIF, which stimulate the expression of endothelial mitogens such as VEGF. Hyperactivation of Akt, in contrast, triggers senescence and apoptotic cell death, thereby preventing tumor progression. These effects involve increased ROS production as well as inhibition of FoxO transcription factors and the subsequent down-regulation of antioxidant enzymes, including sestrin-3, MnSOD, and catalase. Pro-oxidant conditions can activate p53, resulting either in senescence by induction of the Cdk inhibitor p21 or in apoptosis by activation of BH3-only proteins. In addition, the atypical nuclear expression of Akt can induce apoptosis by triggering unscheduled activation of the cell cycle-regulatory kinase Cdk2, either by direct phosphorylation or by induction of p27 degradation. Several interfering pathways and downstream effectors of Akt are omitted for clarity.

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