The pure anti-androgen bicalutamide inhibits cyclin A expression both in androgen-dependent and -independent cell lines.
We investigated the effects of testosterone and the pure anti-androgen, bicalutamide, on DNA synthesis and cell cycle in androgen-sensitive or -insensitive human and mouse cell lines by 3H-thymidine incorporation, flow cytometry, RT-PCR and Western blotting. In androgen-dependent mouse SC-3 cells, testosterone induced DNA synthesis, shift of cell cycle distribution from G0/G1 to S/G2/M and expression of cyclin A. The induction was preceded by that of fibroblast growth factor 8 (FGF-8), and completely blocked by monoclonal antibody to FGF-8. Dihydrotestosterone (DHT) induced cyclin A expression in androgen-sensitive human prostate cancer cells, but not in androgen-independent cell lines. Bicalutamide almost completely inhibited these androgen-dependent effects both in LNCaP and SC-3 cells, but had no or limited effect on androgen-independent or FGF-8-induced DNA synthesis, and FGF-8 induced cyclin A expression. Interestingly, bicalutamide inhibited both DNA synthesis and the cyclin A expression in androgen-independent human cell lines in serum-free condition. A MEK1/2 inhibitor U0126 blocked both androgen- and rFGF-8-induced DNA synthesis. Overall, bicalutamide inhibits the cyclin A expression possibly by inhibiting FGF-8 mRNA expression and FGF-8 protein secretion but not by inhibiting FGF receptor (FGFR) signalling in androgen-dependent cell lines, and by other mechanisms in androgen-independent cell lines. The results suggest that combination with compounds such as FGFR signalling inhibitors may provide additional benefits to anti-androgens. It is also suggested that cyclin A could be a sensitive marker for androgen-induced cancer growth and for the growth inhibitory effects of anti-androgen.
Katayama
Hiroshi
H
Laboratory of Clinical and Experimental Pathophysiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
Murashima
Teruko
T
Saeki
Yoshiko
Y
Nishizawa
Yasuko
Y
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000037:antagonists & inhibitors*; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D013739:Testosterone / Q000494:pharmacology; D013936:Thymidine / Q000737:chemistry; D014105:Tosyl Compounds / Q000494:pharmacology*
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D019925:Cyclin A; C496456:FGF8 protein, human; D009570:Nitriles; D014105:Tosyl Compounds; D051524:Fibroblast Growth Factor 8; D013739:Testosterone; C053541:bicalutamide; D013936:Thymidine