OnlineFirst on September 28 , 2010 as 10 . 1158 / 0008 - 5472 . CAN - 09 - 4729 Cancer esearch cular and Cellular Pathobiology GRP 3 Contributes to Formation and Maintenance of the R state Cancer Phenotype

Downlo GRP3 mediates the activation of the Ras signaling pathway that is present in many human cancers. Here, lored the involvement of RasGRP3 in the formation and maintenance of the prostate cancer phenotype. P3 expression was elevated inmultiple human prostate tumor tissue samples and in the human androgenndent prostate cancer cell lines PC-3 and DU 145 compared with the androgen-dependent prostate cell line LNCaP. Downregulation of endogenous RasGRP3 in PC-3 and DU 145 cells reduced Ras-GTP tion, inhibited cell proliferation, impeded cell migration, and induced apoptosis. Anchorage-independent of the PC-3 cells and tumor formation in mouse xenografts of both cell lines were likewise inhibited. tion of RasGRP3 expression reduced AKT and extracellular signal-regulated kinase 1/2 phosphorylation nsitized the cells to killing by carboplatin. Conversely, exogenous RasGRP3 elevated Ras-GTP, stimulated ration, and provided resistance to phorbol 12-myristate 13-acetate–induced apoptosis in LNCaP cells. P3-overexpressing LNCaP cells displayed a markedly enhanced rate of xenograft tumor formation in both nd female mice compared with the parental line. Suppression of RasGRP3 expression in these cells ed downstream RasGRP3 responses, caused the cells to resume the LNCaP morphology, and suppressed , confirming the functional role of RasGRP3 in the altered behavior of these cells. We conclude that growth RasGRP3 contributes to the malignant phenotype of the prostate cancer cells and may constitute a novel therapeutic target for human prostate cancer. Cancer Res; 70(20); OF1–13. ©2010 AACR.