PKCδ Activation Mediates Angiogenesis via NADPH Oxidase Activity in PC-3 Prostate Cancer Cells

BACKGROUND. PKC delta is generally known as a pro-apoptotic and anti-proliferative enzyme in human prostate cancer cells. METHODS. Here, we investigated the role of PKC delta on the growth of PC-3 human prostate cancer cells in vivo and in vitro. RESULTS. We found that sustained treatment with a specific PKC delta activator (psi delta receptor for active C kinase, psi delta RACK) increased growth of PC-3 xenografts. There was increased levels of HIF-1 alpha, vascular endothelial growth factor and CD31-positive cells in PC-3 xenografts, representative of increased tumor angiogenesis. Mechanistically, PKC delta activation increased the levels of reactive oxygen species (ROS) by binding to and phosphorylating NADPH oxidase, which induced its activity. Also, PKC delta-induced activation of NADPH oxidase increased the level of HIF-1 alpha. CONCLUSIONS. Our results using tumors from the PC-3 xenograft model suggest that PKC delta activation increases angiogenic activity in androgen-independent PC-3 prostate cancer cells by increasing NADPH oxidase activity and HIF-1 alpha levels and thus may partly be responsible for increased angiogenesis in advanced prostate cancer. Prostate 71: 946-954, 2011. (C) 2010 Wiley-Liss, Inc.