THE RON RECEPTOR TYROSINE KINASE POSITIVELY REGULATES ANGIOGENIC CHEMOKINE PRODUCTION IN PROSTATE CANCER CELLS

Overexpression of the Ron receptor tyrosine kinase has recently been shown in a wide variety of human cancers. However, no studies have examined Ron receptor expression or function during prostate tumorigenesis. We report here that Ron is highly expressed in human prostate adenocarcinoma and metastatic lymph nodes compared to normal prostate or benign prostate hyperplasia. Furthermore, we show that Ron is overexpressed in PC-3 and DU145 prostate cancer cell lines, and that levels of angiogenic chemokines produced by prostate cancer cells positively correlates with Ron expression. Knockdown of Ron in PC-3 or DU145 cells results in a significant decrease in angiogenic chemokine production and is associated with decreased activation of the transcription factor NF-kappaB. Moreover, exogenous overexpression of Ron in LNCaP cells is sufficient to induce a significant increase in angiogenic chemokines that can be abrogated by inhibition of NF-kappaB signaling. Given that the function of angiogenic chemokines is important in the development of new blood vessels, we also examined the ability of Ron to modulate endothelial cell migration. Our data show that knockdown of Ron in prostate cancer cells results both in significantly less endothelial cell chemotaxis compared to Ron-expressing cells in vitro as well as in reduced tumor growth and decreased microvessel density following orthotopic transplantation into the prostate in vivo. In total, our data suggest that the Ron receptor is important in modulating prostate tumor growth by modulating angiogenic chemokine production and subsequent endothelial cell recruitment.