title: RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype.
abstract: RasGRP3 mediates the activation of the Ras signaling pathway that is present in many human cancers. Here, we explored the involvement of RasGRP3 in the formation and maintenance of the prostate cancer phenotype. RasGRP3 expression was elevated in multiple human prostate tumor tissue samples and in the human androgen-independent prostate cancer cell lines PC-3 and DU 145 compared with the androgen-dependent prostate cancer cell line LNCaP. Downregulation of endogenous RasGRP3 in PC-3 and DU 145 cells reduced Ras-GTP formation, inhibited cell proliferation, impeded cell migration, and induced apoptosis. Anchorage-independent growth of the PC-3 cells and tumor formation in mouse xenografts of both cell lines were likewise inhibited. Inhibition of RasGRP3 expression reduced AKT and extracellular signal-regulated kinase 1/2 phosphorylation and sensitized the cells to killing by carboplatin. Conversely, exogenous RasGRP3 elevated Ras-GTP, stimulated proliferation, and provided resistance to phorbol 12-myristate 13-acetate-induced apoptosis in LNCaP cells. RasGRP3-overexpressing LNCaP cells displayed a markedly enhanced rate of xenograft tumor formation in both male and female mice compared with the parental line. Suppression of RasGRP3 expression in these cells inhibited downstream RasGRP3 responses, caused the cells to resume the LNCaP morphology, and suppressed growth, confirming the functional role of RasGRP3 in the altered behavior of these cells. We conclude that RasGRP3 contributes to the malignant phenotype of the prostate cancer cells and may constitute a novel therapeutic target for human prostate cancer.
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255 , USA.
authors.forename: Dazhi
authors.initials: D
authors.lastname: Yang
authors.forename: Noemi
authors.initials: N
authors.lastname: Kedei
authors.forename: Luowei
authors.initials: L
authors.lastname: Li
authors.forename: Juan
authors.initials: J
authors.lastname: Tao
authors.forename: Julia F
authors.initials: JF
authors.lastname: Velasquez
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Michalowski
authors.forename: Balázs I
authors.initials: BI
authors.lastname: Tóth
authors.forename: Rita
authors.initials: R
authors.lastname: Marincsák
authors.forename: Attila
authors.initials: A
authors.lastname: Varga
authors.forename: Tamás
authors.initials: T
authors.lastname: Bíró
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Yuspa
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
mesh_terms: D002455:Cell Division; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020663:ras Guanine Nucleotide Exchange Factors
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C413212:RASGRP3 protein, human; D012334:RNA, Neoplasm; D020663:ras Guanine Nucleotide Exchange Factors