title: The pro-survival function of Akt kinase can be overridden or altered to contribute to induction of apoptosis.
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 pro-apoptotic 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.
authors.affiliation: Department of Gynecologic Oncology, University of Oklahoma Health Sciences Centre, Oklahoma City, Oklahoma, 73104, USA. Doris-Benbrook@ouhsc.edu
authors.forename: Doris Mangiaracina
authors.initials: DM
authors.lastname: Benbrook
authors.forename: Chioniso Patience
authors.initials: CP
authors.lastname: Masamha
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D051057:Proto-Oncogene Proteins c-akt