Role of PI3 kinase/AKT2 signaling in ovarian oncogenesis

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DESCRIPTION: (Applicant's Description) AKT2 is a member of the Akt/protein kinase B family and is activated in response to phosphatidylinositol 3-kinase (PI 3-K)-mediated signals triggered at the cell membrane by growth factors. Amplification and/or overexpression of the AKT2 oncogene are associated with the development of human ovarian carcinomas. Therefore, understanding the role of AKT2 and PI 3-K-mediated signals in the growth regulation of human ovarian surface epithelial (HOSE) cells will contribute to a better understanding of the molecular mechanisms underlying ovarian oncogenesis, which is the broad, long-term objective of this project. The specific aims are: (1) Determine the involvement of AKT2, the related AKT1, and PI 3-K in human ovarian cancer. Examine the expression/kinase activity of AKT2, AKT1, and the catalytic subunit of PI 3-K (p110 alpha) in ovarian carcinoma specimens, and their expression in premalignant lesions in women predisposed to ovarian cancer. Correlate these laboratory findings with various clinicopathologic parameters to determine their clinical relevance. (2) Characterize the role of AKT2 in the regulation of physiological and neoplastic growth of HOSE cells in vitro. Evaluate the effect of the expression and/or activity of AKT2 on growth rate, cell cycle progression, and the induction of apoptosis. Using cDNA expression arrays, identify groups of genes associated with ovarian oncogenesis, whose expression is regulated in response to AKT2 expression/activity. (3) Determine the role of AKT2 in invasion and metastasis of HOSE cells and ovarian cancer cells. Using conditional retroviral expression constructs, investigate the potential involvement of AKT2 expression/activity in cell survival and the development of more invasive or metastatic phenotypes. (4) Identify modulators and substrates of AKT2. Using the yeast two-hybrid system and ovarian cancer-specific phage cDNA expression libraries, identify proteins that interact with AKT2 in the transduction of mitogenic signals in ovarian cancer cells, and determine the physiological significance of these interactions in HOSE cells. Overall, the studies proposed here will provide important new insights regarding the mechanisms by which AKT2 and PI 3-K-mediated signals contribute to ovarian oncogenesis, and may create potential avenues for therapeutic intervention.