Role of p115RhoGEF in the regulation of extracellular Ca(2+)-induced choline kinase activation and prostate cancer cell proliferation.

Ca(2+) is a ubiquitous cellular signal which plays a central role in the regulation of cell function. To understand aberrant signaling through the Ca(2+)-sensing receptor (CaR) in prostate cancer cells, we compared expression of CaR signaling components in human nonmalignant prostate epithelial cells and several prostate cancer cell lines, as well as normal human prostate and prostate tumor specimens. We found that levels of the CaR, Gα(12) and p115RhoGEF expression are significantly up-regulated in more tumorigenic prostate cancer cells and prostate tumor specimens. By silencing CaR, Gα(12), p115RhoGEF or choline kinase (ChoK) expression, analyzing the change in lipid profiles, blocking signaling pathways using chemical inhibitors, and co-immunoprecipitating the relevant signaling proteins, we demonstrate that p115RhoGEF, a regulator of G protein signaling (RGS) with GAP activity for Gα(12/13) and with guanine nucleotide exchange activity for the small G protein Rho, plays an important role in the regulation of Ca(o)(2+)-induced ChoK activation and cell proliferation in more tumorigenic prostate cancer cell lines. The results demonstrate an important role of p115RhoGEF in prostate tumorigenesis and provide a potential target of cancer therapeutics.