RhoC Promotes Metastasis via Activation of the Pyk2 Pathway in Prostate Cancer

RhoC is one of the Ras-homologous family genes which has been implicated in tumorigenesis and tumor progression. However, the exact role of RhoC is controversial and yet to be clarified. We have examined the effect of RhoC on prostate tumor cells and found that RhoC had no effect on cell proliferation in vitro or tumor growth in mice. However, RhoC significantly enhanced the metastatic ability of the tumor cells in these animals, suggesting that RhoC affects only metastases but not growth of prostate tumor cells. The results of our immunohistochemical analyses on tumor specimens from 63 prostate cancer patients indicate that RhoC expression had no significant correlation with Gleason grade. However, the expression of RhoC showed significant positive correlation with both lymph-node and distant metastasis, and it was inversely correlated to patient survival. We also found that RhoC significantly augmented the ability of invasion and motility of prostate tumor cells by activating MMP2 and MMP9 in vitro. The results of our antibody array analysis for signal molecules revealed that RhoC significantly activated kinases including MAPK, FAK, Akt and Pyk2. Inhibition of Pyk2 kinase blocked the RhoC-dependent activation of FAK, MAPK and Akt followed by suppression of MMP2 and MMP9. Inhibitors of both MAPK and Akt also significantly blocked activities of these matrix metalloproteinases. Therefore, our results indicate that RhoC promotes tumor metastases in prostate cancer by sequential activation of Pyk2, FAK, MAPK and Akt followed by up-regulation of MMP2 and MMP9, which results in stimulation of invasiveness of tumor cells.