Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines.
Bicalutamide is a non-steroidal anti-androgen commonly used in the treatment of prostate carcinoma. We analysed the transcriptional response to bicalutamide treatment with the aim of explaining the inhibition of telomerase in the androgen-sensitive cell line LNCaP and the effects of bicalutamide on the androgen-insensitive cell line DU145. Cells treated with 80 muM bicalutamide in steroid-depleted medium for 1 day were analysed in duplicate by Affymetrix Human Genome Focus Arrays. Response to bicalutamide in LNCaP cells was represented by downregulation of androgen-regulated genes, activation of the p53 pathway and inhibition of telomerase, which was associated with downregulation of v-myc avian myelocytomatosis viral oncogene homologue (MYC) and telomerase reverse transcriptase subunit. In DU145 cells we observed the influence of cell density on bicalutamide effectivity such that highly confluent cells showed lesser sensitivity than low confluent ones. In conclusion, we provide an explanation for telomerase inhibition after androgen receptor blockade in LNCaP cells and we also report activation of the p53 pathway in LNCaP cells and in-vitro sensitivity to bicalutamide of low confluent androgen-insensitive DU145 cells. These findings might have implications for both experimental and clinical research into prostate cancer. In particular, activation of the p53 pathway after treatment with 80 microM bicalutamide could justify usage of bicalutamide dosages higher than 150 mg daily in androgen-sensitive carcinoma therapy.
Bouchal
Jan
J
Laboratory of Molecular Pathology and Institute of Pathology, Palacký University, Hnevotínská 3, 775 15 Olomouc, Czech Republic. bouchal@tunw.upol.cz
Baumforth
Karl R N
KR
Sváchová
Michaela
M
Murray
Paul G
PG
von Angerer
Erwin
E
Kolár
Zdenek
Z
D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects*; D006801:Humans; D008297:Male; D009570:Nitriles; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles; D014105:Tosyl Compounds
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D009570:Nitriles; D013778:Tetrazolium Salts; D013844:Thiazoles; D014105:Tosyl Compounds; D012313:RNA; C053541:bicalutamide; D019098:Telomerase; C022616:thiazolyl blue