Phosphatidylinositol 3-kinase/Akt signaling pathway and angiogenesis

Angiogenesis, the formation of new blood vessels from preexisting ones, is tightly controlled under physiological conditions, and deregulated angiogenesis contributes to many pathological situations. This study investigates the role of PI3K/Akt pathway in both physiological and pathological angiogenesis. Angiopoietin-1 (Ang1) is an endothelial specific growth factor that plays a critical role in vessel maturation and stabilization during angiogenesis. We found that Ang1 potently induced p70S6K1 activation in human umbilical vein endothelial cells (HUVECs). p70S6K1 is a downstream target of PI3K, but its role in angiogenesis has not be defined. In the work shown in Chapter 2, p70S6K1 activity in HUVECs was modified by adenovirus-mediated gene transfer, and we provided first evidence that p70S6K1 is directly involved in Ang1-induced angiogenic endothelial responses, including cell migration, invasion, survival, and capillary morphogenesis. We also examined the effect and mechanisms of action of insulin-like growth factor-I (IGF-I) on the expression of cyclooxygenase-2 (COX-2), which is a crucial player in angiogenesis and tumorigenesis. In Chapter 3, we showed that IGF-I efficiently upregulated COX-2 expression in human ovarian cancer cells, which was differentially regulated by PI3K, MAPK, and PKC signaling pathways at transcriptional and/or post-transcriptional levels. In the study shown in Chapter 4, we selectively modulated PI3K/Akt signaling in either human microvascular endothelial cells or cancer cells, and examined the effects on tumor angiogenesis using a chimeric tumor model. We found that PI3K and Akt activities in both endothelial cells and tumor cells contributed to tumor growth and angiogenesis, suggesting that targeting PI3K/Akt signaling in both cellular compartments may be more effective for anti-cancer therapy. In Chapter 5, we demonstrated that resveratrol has a strong inhibitory effects on hypoxiainducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) expression in human ovarian cancer cells. The effects are associated with suppression of PI3K/Akt and MAPK pathways, interference with protein translational machinery, and enhancement of HIF-1alpha protein degradation through the proteasome. This work provides a better understanding of the molecular basis of angiogenesis, which we hope may facilitate the identification of novel therapeutic targets in the future