title: Zoledronic acid mediates Ras-independent growth inhibition of prostate cancer cells.
abstract: Zoledronic acid (ZOL), the most potent known bisphosphonate, is clinically efficacious against advanced prostate cancer, although the molecular mechanism by which bisphosphonates prevent prostate cancer cell growth remains unknown. Because Ras is the most thoroughly characterized member of the small G-proteins involved in the regulation of many cellular functions including several oncogenic pathways, the aim of this study was to clarify whether Ras is the molecular target of ZOL in prostate cancer cells. The prostate cancer cell lines PC-3, DU145, and LNCaP were used. Cell proliferation was determined by a modified MTT assay. Geranylgeranyol (GGOH) and famesol (FOH) were used as analogues of geranylgeranyl-pyrophosphate and farnesyl-pyrophosphate, respectively. Changes in expression and/or membrane localization of Ras, Rap1, and phosphorylated MAPK were evaluated by Western blotting. ZOL mediated growth inhibition of prostate cancer cells in a dose- and time-dependent manner. The ZOL-induced growth inhibitory effect was circumvented by the addition of GGOH. In contrast, FOH did not reverse the growth inhibitory effect of ZOL. The amount of membrane-anchored Ras was clearly independent of ZOL-mediated growth inhibition. Unexpectedly, ZOL induced N- and H-Ras expression of the cytosolic fraction. Ras does not appear to be the molecular target for ZOL-induced growth inhibition. Prevention of geranylgeranylation rather than farnesylation is an important therapeutic target in prostate cancer.
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nogawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Segawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sato
authors.forename: Asumi
authors.initials: A
authors.lastname: Yokota
authors.forename: Mitsutera
authors.initials: M
authors.lastname: Koizumi
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D004164:Diphosphonates / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D017368:Protein Prenylation; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid