The Pro-Survival Function of Akt Kinase can be Overridden or Altered to Contribute to Induction of Apoptosis

D.      M. Benbrook; C.      P. Masamha

Abstract

The Serine/Threonine protein kinase B (PKB), which is now called Akt, has well-documented oncogenic potential and pro-survival activities that can counteract apoptosis induced by anti-cancer drugs. The goal of this review is to discuss current evidence that the pro-survival function of Akt can be overridden or converted to a pro-apoptotic function. A brief description of how upstream regulators and downstream effectors of the Akt kinase participate in a network of protection against cell death is presented. This background provides a basis for understanding how specific chemotherapeutic agents and cellular conditions can overcome the Akt pro-survival signal or alter Akt signaling in a way that converts Akt kinase activity to be directly involved in the induction of apoptosis. This pro-apoptotic activity only occurs under specific cellular conditions, since Akt can function as both a survival factor and an apoptotic factor within the same cell type. In some situations, the Akt pro-survival activity was eventually overwhelmed by prolonged treatment with chemotherapeutic agents, or was converted to a pro-apoptotic function upon prolonged hyperactivation of the Akt kinase activity, or by nuclear retention or unbalanced phosphorylation of the Akt protein. Increased levels of intracellular oxidation stimulated Akt activity and were increased by oxidative metabolism resulting from chronic Akt hyperactivity. Downstream effects on mTOR, FoxO3 transcription factors and cdk-2 affected the switch between pro-survival and proapoptotic functions through complex positive- and negative-feedback interactions. Upstream, caveolin-1 stimulated the pro-apoptotic function. Implications of the opposing functions of Akt in cancer therapy are discussed.

Keywords: Akt, Apoptosis, caveolin, cyclin dependent kinase-2, FoxO transcription factors, mammalian target of rapamycin, phosphorylation, reactive oxygen species, Ataxia telangiectasia mutated, Cyclin dependent kinase 2, Extracellular signal-regulated kinase, Insulin-like growth factor receptor, Manganese superoxide dismutase, Superoxide dismutase, Regulatory associated protein of mTOR