Attenuation of Ras signaling restores androgen sensitivity to hormone-refractory C4-2 prostate cancer cells.
Progression of prostate cancer to androgen-refractory disease is correlated with increased expression of growth factors and receptors capable of establishing autocrine and/or paracrine growth-stimulatory loops. Many of these growth factor receptors engage Ras as part of their normal signaling activities, raising the possibility that activation of endogenous c-Ras could be a common mechanism for prostate cancer progression. Here we demonstrate that inducible expression of a dominant negative form of Ras restores androgen sensitivity to a hormone-refractory prostate cancer cell line. We show that expression of RasN17 in the hormone-refractory C4-2 cell line enhances in vitro sensitivity to the growth-inhibitory action of the antiandrogen Casodex and inhibits anchorage-independent cell growth. Moreover, although induction of RasN17 by itself has no observable effect on the growth of C4-2 xenografts in intact male mice, it restores androgen dependence to the C4-2 xenografts so that they dramatically regress after surgical androgen ablation.
Bakin
Robert E
RE
Department of Microbiology, Cancer Center and Paul Mellon Prostate Cancer Institute, Charlottesville, Virginia 22908, USA.
Gioeli
Daniel
D
Bissonette
Eric A
EA
Weber
Michael J
MJ
D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D009570:Nitriles; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D015398:Signal Transduction; D014105:Tosyl Compounds; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D014105:Tosyl Compounds; C053541:bicalutamide; D017430:Prostate-Specific Antigen; D018631:ras Proteins