The Akt Pathway: Molecular Targets for Anti-Cancer Drug Development

Abstract

The serine/threonine kinase Akt functions intracellularly as a cardinal nodal point for a constellation of converging upstream signaling pathways, which involve stimulation of receptor tyrosine kinases such as IGF-1R, HER2/Neu, VEGF-R, PDGF-R), and an assembly of membrane-localized complexes of receptor-PI-3K and activation of Akt through the second messenger PIP(3). The integration of these intracellular signals at the level of Akt and its kinase activity, regulates the phosphorylation of its several downstream effectors, such as NF-kappa B, mTOR, Forkhead, Bad, GSK-3 and MDM-2. These phosphorylation events in turn mediate the effects of Akt on cell growth, proliferation, protection from pro-apoptotic stimuli, and stimulation of neo-angiogenesis. Because Akt and its upstream regulators are deregulated in a wide range of solid tumors and hematologic malignancies, and in view of the aforementioned biologic sequelae of this pathway, the Akt pathway is considered a key determinant of biologic aggressiveness of these tumors, and a major potential target for novel anti-cancer therapies. This review focuses on ongoing translational efforts to therapeutically target Akt and its biologic sequelae, either at the level of Akt itself or at the levels of its upstream regulators and downstream effectors. Because Akt is also important for proliferative and anti-apoptotic signaling pathways critical for normal cells, particular emphasis is placed on the fine-tuning the targeting of individual components of this pathway to maximize the therapeutic index of anti-cancer strategies based on the PI-3K/Akt pathway.

Interleukin 3 and schizophrenia: the impact of sex and family history

“…First, IL3 is the upstream signal that activates the Akt1/Gsk3b apoptotic pathway. 61 Imbalance of apoptosis in the early stages of development of the central nervous system has been suggested as a cause of schizophrenia. 14,62 Indeed, a higher Bax/Bcl-2 ratio, an index of apoptotic activation, is observed in schizophrenia patients.…”

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…Akt isoforms are overexpressed in a variety of human tumors, and, at the genomic level, are amplified in gastric adenocarcinomas (Akt1), ovarian (Akt2), pancreatic (Akt2) and breast (Akt2) cancers (Hill and Hemmings, 2002;Mitsiades et al, 2004). In addition, many tumor cells display elevated levels of PI3K enzymatic products as a result of deletion/mutations of PTEN, activation of Ras or expression of autocrine growth factors (Maira et al, 2008b).…”

Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells

“…When activated, these PI 3-Ks convert the substrate phosphatidylinositol-4,5-bisphosphate (PI 4,5-P 2 ) into the second messenger phosphatidylinositol 3,4,5-triphosphate (PI 3,4, ). Accumulation of PI 3,4,5-P 3 causes the phosphorylation and activation of the serine/threonine kinase PKB (also termed Akt), as well as the phosphorylation and inactivation of downstream PKB targets, including Bad, GSK3 and FoxO proteins, which have a negative role in cell survival (Mitsiades et al, 2004). FoxO (Forkhead box, class O) is a newly characterized subfamily of the Forkhead/winged helix (Fox) group of transcription factors, which play a predominant role in mediating the proliferative and survival function of the PI 3-K/PKB signalling pathway Burgering and Medema, 2003).…”