Angiotensin II Up-Regulates PAX2 Oncogene Expression and Activity in Prostate Cancer Via the Angiotensin II Type I Receptor

BACKGROUND. Paired homeobox 2 gene (PAX2) is a transcriptional regulator, aberrantly expressed in prostate cancer cells and its down-regulation promotes cell death in these cells. The molecular mechanisms of tumor progression by PAX2 over-expression are still unclear. However, it has been reported that angiotensin-II (A-II) induces cell growth in prostate cancer via A-II type I receptor (AT1R) and is mediated by the phosphorylation of mitogen activated protein kinase (MAPK) as well as signal transducer and activator of transcription 3 (STAT3). METHODS. Here we have demonstrated that A-II Lip-regulates PAX2 expression in prostate epithelial cells and prostate cancer cell lines resulting in increased cell growth. Furthermore, AT1R receptor antagonist losartan was shown to inhibit A-II induced PAX2 expression in prostate cancer. Moreover, analysis using pharmacological inhibitors against MEK1/2, ERK1/2, JAK-II, and phospho-STAT3 demonstrated that AT1R-mediated stimulatory effect of A-II on PAX2 expression was regulated in part by the phosphorylation of ERK1/2, JAK II, and STAT3 pathways. In addition, we have showed that down-regulation of PAX2 by ail AT1R antagonist as well as JAK-II and STAT3 inhibitors suppress prostate cancer cell growth. RESULTS. Collectively, these findings show for the first time that the renin-angiotensin system (RAS) may promote prostate tumorigenesis via up-regulation of PAX2 expression. CONCLUSIONS. Therefore, PAX2 may be a novel therapeutic target for the treatment of carcinomas such as prostate cancer via the clown-regulation of its expression by targeting the AT1R signaling pathways. Prostate 69:1334-1342, 2009. (C) 2009 Wiley-Liss, Inc.