Potential of Akt mediated DNA repair in radioresistance of solid tumors overexpressing erbB-PI3K-Akt pathway
Phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a key cascade downstream of several membrane-bound receptors, especially receptor tyrosine kinases such as erbB family members. This pathway is the most frequently activated pathway in human solid tumors. Akt/PKB (Protein Kinase B) members are the major kinases downstream of PI3K which are involved in a variety of cellular functions including growth, proliferation, survival, invasion, metastasis, and angiogenesis. Accumulated evidence indicates that activated Akt is a major predictive marker for the radiation response. Radiation-induced DNA double-strand break (DNA-DSB) is the prime cause of cell death induced by ionizing radiation. Preclinical in vitro and in vivo studies have shown that activated Akt1 accelerates repair of IR-induced DNA double-strand breaks (DNA-DSB) and, consequently, improves post-irradiation cell survival. Analyzing disregulations of Akt such as point mutations, gene amplification or overexpression, which result in constitutive activation of Akt might be of special importance in the context of radiotherapy outcome. Such studies as well as the mechanism(s) by which activated Akt1 regulates repair of DNA-DSB might help to combine the appropriate molecular targeting strategies with conventional radiotherapy to overcome radioresistance in solid tumors. Thus, in this review we discuss the disregulations in the components of upstream regulators of Akt as well as those specific modifications of AKT isoforms which enhance Akt activity. Likewise, mechanisms by which Akt improves post-irradiation cell survival will be reviewed. In this context, the role of Akt1 in repair of radiation-induced DNA-DSB will be discussed in more detail.