The AKT Signaling Pathway

Growth factors, oncogenic Ras, and integrins could activate this survival pathway. Once activated, the phosphatidylinositol-3 kinase (PI3K) facilitates the conversion of PIP2 to PIP3, which then activates the transcription factor AKT. This has been shown to promote transcription of antiapoptotic Bcl-XL and inactivate Bad, caspase-9 and FKHRL1 (an inducer ofmany proapoptotic factors) (83). A tumor suppressor, phosphatase and ten-sin homolog (PTEN), is regulatory and counteracts AKT by phosphorylating PIP3. AKT is constitutively activated in a wide range of tumors such as prostate, liver, lung, ovary, and breast carcinomas (84). Also, this pathway has been observed to cause resistance to chemotherapy; one example is inhibition of cisplatin-induced apoptosis in ovarian carcinoma through phosphorylation ofthe proapoptotic Bad. Treatment with either the AKT inhibitor wortmannin or exogenous expression of a dominant-negative AKT sensitized the cells to cisplatin (85). Another successful approach in AKT inhibition is the compound genistein, which potentiates TRAIL-induced apoptosis in breast cancer cells (86). Yet another compound, rapamycin, targets mTOR kinase that is activated by AKT and has demonstrated activity in cancers with mutations in PTEN, such as glioblastoma, prostate, and breast carcinomas (87,88).

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