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The Oncogene Phosphatidylinositol 3'-Kinase Catalytic Subunit Promotes Angiogenesis via Vascular Endothelial Growth Factor in Ovarian Carcinoma¹

Abramson Family Cancer Research Institute [L. Z., G. C.], Center for Research on Reproduction and Women’s Health [L. Z., W. H., J-W. P., C. V., W. Y., G. C.], Division of Gynecologic Oncology, Department of Obstetrics and Gynecology [S. C. R., G. C.], and Cell and Molecular Biology Program and Department of Genetics [N. Y.], University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and Department of Obstetrics and Gynecology, University of Turin, Turino, Italy [D. K., S. F., I. A. R. d. l. L.]

The gene of phosphatidylinositol 3-kinase catalytic subunit (PIK3CA) has been implicated as an oncogene in ovarian cancer [L. Shayesteh et al., Nat. Genet., 21: 99–102, 1999]. In this study, we examined the expression of PIK3CA mRNA and its p110 protein product in human ovarian carcinoma and investigated its role in regulating angiogenesis via vascular endothelial growth factor (VEGF). PIK3CA mRNA was detected in 66.6% of stage I and 93.9% of advanced stage ovarian cancer specimens and in all 17 ovarian cancer cell lines. PIK3CA mRNA levels were significantly higher in invasive carcinomas compared with benign and low malignant potential neoplasms (P = 0.007), but no significant difference was seen between early and advanced stage carcinomas (P = 0.812). Strong expression of immunoreactive p110 was detected in tumor cells and/or stroma endothelium. PIK3CA expression in vivo positively correlated, both at the mRNA and the protein level, with the expression of VEGF as well as with the extent of microvascular development. Furthermore, PIK3CA mRNA overexpression positively correlated with increased proliferation and decreased apoptosis of tumor cells in vivo. In vitro, PIK3CA expression positively correlated with the expression of VEGF in ovarian cancer cells, whereas the phosphatidylinositol 3'-kinase inhibitor Ly294002 reduced both the constitutive and inducible expression of hypoxia-inducible factor-1 at the mRNA and protein levels and abrogated VEGF up-regulation by glucose starvation. Furthermore, Ly294002 suppressed cell proliferation and, at higher doses, induced marked apoptosis in ovarian cancer cells. Collectively, these data strongly indicate that PIK3CA supports ovarian cancer growth through multiple and independent pathways affecting cell proliferation, apoptosis and angiogenesis, and plays an important role in ovarian cancer progression.

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