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Scientifica  2013 

The Role of the Dysfunctional Akt-Related Pathway in Cancer: Establishment and Maintenance of a Malignant Cell Phenotype, Resistance to Therapy, and Future Strategies for Drug Development

DOI: 10.1155/2013/317186

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Abstract:

Akt serine/threonine kinases, or PKB, are key players in the regulation of a wide variety of cellular activities, such as growth, proliferation, protection from apoptotic injuries, control of DNA damage responses and genome stability, metabolism, migration, and angiogenesis. The Akt-related pathway responds to the stimulation mediated by growth factors, cytokines, hormones, and several nutrients. Akt is present in three isoforms: Akt1, Akt2, and Akt3, which may be alternatively named PKBα, PKBβ, and PKBγ, respectively. The Akt isoforms are encoded on three diverse chromosomes and their biological functions are predominantly distinct. Deregulations in the Akt-related pathway were observed in many human maladies, including cancer, cardiopathies, neurological diseases, and type-2 diabetes. This review discusses the significance of the abnormal activities of the Akt axis in promoting and sustaining malignancies, along with the development of tumor cell populations that exhibit enhanced resistance to chemo- and/or radiotherapy. This occurrence may be responsible for the relapse of the disease, which is unfortunately very often related to fatal consequences in patients. 1. Introduction Akt serine/threonine protein kinases are also termed PKB and constitute fundamental intracellular signaling systems for the regulation of an ample assortment of cellular and physiological activities, such as cell growth, proliferation, protection from apoptosis, modulation of DNA damage response and genome stability, motility, angiogenesis, and metabolism [1–7]. These Akt-mediated cellular functions are regulated by various types of external stimuli, which derive from the interaction of growth factors, hormones, cytokines, and nutrients with specific cellular receptors [1–7]. Some of the main hormones and growth factors that have the ability to stimulate the Akt axis comprise epidermal growth factor (EGF), insulin, insulin-like growth factor-I (IGF-I), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF) [1–6]. Basically, the interaction between the external factors and the Akt axis occurs via ligand-cellular receptor binding, which, in turn, results in the transient Akt phosphorylation, with consequent temporary activation of the Akt intracellular signaling system. Overall, the Akt stimulation mediated by growth factors regulates cell cycle transition from G1/S to G2/M phase [1–7]. In addition, the Akt-related pathway comes into play in the orchestration of the DNA damage response and cellular genome stability [7]. Intracellular upstream effectors that

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