Steroidogenesis inhibitors alter but do not eliminate androgen synthesis mechanisms during progression to castration-resistance in LNCaP prostate xenografts.
In castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. We and others have recently reported that CRPC tumor cells can de novo synthesize androgens from adrenal steroid precursors or cholesterol and that high levels of progesterone exist in LNCaP tumors after castration serving perhaps as an intermediate in androgen synthesis. Herein, we compare androgen synthesis from [(3)H-progesterone] in the presence of specific steroidogenesis inhibitors and anti-androgens in steroid starved LNCaP cells and CRPC tumors. Similarly, we compare steroid profiles in LNCaP tumors at different stages of CRPC progression. Steroidogenesis inhibitors targeting CYP17A1 and SRD5A2 significantly altered but did not eliminate androgen synthesis from progesterone in steroid starved LNCaP cells and CRPC tumors. Upon exposure to inhibitors of steroidogenesis prostate cancer cells adapt gradually during CRPC progression to synthesize DHT in a compensatory manner through alternative feed-forward mechanisms. Furthermore, tumors obtained immediately after castration are significantly less efficient at metabolizing progesterone ( approximately 36%) and produce a different steroid profile to CRPC tumors. Optimal targeting of the androgen axis may be most effective when tumors are least efficient at synthesizing androgens. Confirmatory studies in humans are required to validate these findings.
Locke
Jennifer A
JA
The Prostate Centre at Vancouver General Hospital and Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
Nelson
Colleen C
CC
Adomat
Hans H
HH
Hendy
Stephen C
SC
Gleave
Martin E
ME
Guns
Emma S Tomlinson
ES
D000726:Androgen Antagonists / Q000378:metabolism; D000728:Androgens / Q000096:biosynthesis* / Q000737:chemistry; D000813:Anilides; D000818:Animals; D002369:Castration; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000378:metabolism; D018450:Disease Progression; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000378:metabolism; D018120:Finasteride / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007654:Ketoconazole / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015735:Mifepristone / Q000378:metabolism; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009570:Nitriles; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology / Q000503:physiopathology; D013256:Steroids / Q000096:biosynthesis* / Q000737:chemistry; D014105:Tosyl Compounds; D014183:Transplantation, Heterologous
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D002934:Cinnamates; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D009570:Nitriles; D013256:Steroids; D014105:Tosyl Compounds; C029010:cinnamic acid; D015735:Mifepristone; D011374:Progesterone; D018120:Finasteride; C053541:bicalutamide; D007654:Ketoconazole