Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer.
The metabolic pathways of androgens and processes by which androgens induce re-growth after androgen deprivation therapy in prostate cancer have not been fully elucidated. In this study, finasteride decreased PSA secretion in medium containing testosterone, androstenedione, androstenediol and dehydroepiandrosterone, whereas dihydrotestosterone (DHT)- and hydroxy-flutamide-induced PSA production was not inhibited by finasteride in LNCaP-FGC cells. The present data show that adrenal androgen precursors do not directly interact with androgen receptors (ARs) but are converted to DHT via the intraprostatic metabolic pathways, resulting in the induction of LNCaP activity. This is the first report confirming this mechanism experimentally and also suggest the use of combined therapies that target ARs and prevent the formation of DHT within prostate cancer cells to achieve optimal therapeutic efficacy.
Suzuki
K
K
Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Science, Asahimachi 1-757, Niigata 951-8510, Japan. kazuyas@med.niigata-u.ac.jp
Nishiyama
T
T
Hara
N
N
Yamana
K
K
Takahashi
K
K
Labrie
F
F
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism*; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000728:Androgens; D004791:Enzyme Inhibitors; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D017430:Prostate-Specific Antigen