PI-3 KINASE PATHWAY IN OVARIAN CANCER

University Of California San Francisco, San Francisco CA

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Abstract

Phosphatidylinositol 3-kinase (PI3K) plays a central role in cellular proliferation, motility, neovascularization, viability, and senescence. PI3K and PTEN a multi-functional phosphatase tumor suppressor identified at the MD Anderson Cancer Center, phosphorylate and dephosphorylate the same site on the inositol ring of membrane phosphatidylinositols (PtdIns). Thus the PI3K signaling cascade may play a critical role in tumorigenesis, invasion and metastases. Using comparative genomic hybridization (CGH), we observed frequent amplification of 3q26 in serous epithelial ovarian cancer but not in cancers from several other lineages. We have demonstrated that the gene encoding the p110alpha catalytic subu7nit of PI3K, located at 3q26.3, is frequently increased in copy number, protein level and enzyme activity in serous epithelial ovarian cancers. Additional components of the PI3K signaling cascade, including p110beta, the p85beta regulatory subunit of PI3K and the AKT1 and AKT2 downstream targets of PI3K are also increased in copy number and, at least in some cases, protein levels in ovarian cancers. PTEN is frequently mutated in endometroid epithelial ovarian cancers. Treatment of ovarian cancer cells with increased p100alpha copy number, with the PI3K inhibitor, LY2P4002, markedly decreases cell proliferation and induces apoptosis in vitro and in vivo. Thus the PI3K pathway appears critically important in ovarian cancer pathogenesis. Abnormalities in the PI3K signaling cascade renders ovarian cancer cells more sensitive to stimulation by extracellular ligands including acid (LPA) and members of the human epidermal growth factor (EGF) family. These G protein- and tyrosine kinase-coupled receptors exhibit pleiomorphic effects on ovarian cancer cells inducing cellular proliferation, preventing apoptosis increasing invasiveness and activating components of the metastases cascade, suggesting a mechanism by which abnormalities in the PI3K cascade contribute to the pathogenesis of ovarian cancer. Understanding the mechanism by which abnormalities in the PI3K cascade contribute to ovarian cancer pathogenesis could lead to an improved understanding of the initiation and progression of ovarian cancer and thus new targets for therapy. To accomplish this, we will. 1. Determine the role of abnormalities in the PI3K pathway in ovarian pathogenesis 2. Determine the effect of abnormalities in the PI3K pathway on responsiveness to growth factors. 3. Identify mechanisms regulating signaling through the PI3K cascade in ovarian cancer cells.