Effect of the hsp90 inhibitor geldanamycin on androgen response of prostate cancer under hypoxic conditions.
OBJECTIVE
To investigate the androgen response of hormone-dependent prostate cancer cells under hypoxia and to examine the effect of geldanamycin (GA), a heat shock protein 90 (Hsp90)-specific inhibitor, on the androgen response.


METHODS
LNCaP cells were cultured with or without GA under normoxic or hypoxic conditions. Cell viability was examined in response to dihydrotestosterone (DHT). Luciferase reporter gene assay was used to measure androgen response element (ARE)- and hypoxia response element (HRE)-mediated transcriptional activities. Western blot was used to analyze the protein levels of androgen receptor (AR), hypoxia-inducible factor-1alpha (HIF-1alpha) and Hsp90.


RESULTS
The DHT-dependent growth and ARE-mediated transcriptional activities of LNCaP cells were depressed under hypoxic conditions. However, these effects were recovered after incubation with GA. In contrast, hypoxia-induced HRE-mediated transcriptional activity, which was dose-dependently increased by DHT, was suppressed by GA. The expression of AR, HIF-1alpha and Hsp90 proteins were decreased under hypoxic conditions by adding GA.


CONCLUSIONS
Geldanamycin increases the androgen response regardless of AR protein in hormone-dependent prostate cancer cells under hypoxic conditions.
Suzuki
Yasutomo
Y
Department of Urology, Nippon Medical School, Showa University, Tokyo, Japan. yasu17@nms.ac.jp
Kondo
Yukihiro
Y
Hara
Shuntaro
S
Kimata
Ryouji
R
Nishimura
Taiji
T
D000728:Androgens / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects
D000728:Androgens; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; C497442:HIF1A protein, human; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; D011944:Receptors, Androgen; C001277:geldanamycin