Recent studies demonstrate that PI3K activation and PTEN mutation are frequently found in many human cancer cells and tissues. However, the mechanism of PI3K signaling in human cancer tumorigenesis remains to be elucidated. In this study we specifically downregulated p110α expression in ovarian cancer cells using siRNA interference. We found that p110α downregulation greatly decreased ovarian tumor growth and angiogenesis, and that p110α siRNA inhibited VEGF expression through decreasing hypoxia-inducible factor 1α expression in both ovarian cancer cells and tumor tissues. To determine the downstream targets of PI3K in regulating tumor growth and angiogenesis, we find that AKT1 is a major downstream mediator for regulating tumor growth, angiogenesis, and VEGF expression. These data show that p110α and AKT1 play an important role in tumor growth by inducing angiogenesis and by increasing HIF-1α and VEGF expression. This work provides a better understanding of the molecular mechanism of human cancer induced by the activation of PI3K signaling. J. Cell. Physiol. 209: 56–66, 2006. © 2006 Wiley-Liss, Inc.