UroToday - It is known that in castration-resistant prostate cancer (CRPC) the androgen receptor (AR) is expressed and remains active and prostate cancer (CaP) cells are able to produce their own supply of androgens. These intracrine androgens are synthesized by the increased activity of steroidogenic enzymes that use cholesterol precursors. Cholesterol is a critical cellular molecule that is involved in many cellular processes. Cells obtain cholesterol from both exogenous uptake and endogenous synthesis. In the online edition of Prostate, Dr. Carlos Leon and associates from the University of British Columbia and Brisbane, Australia investigate how cholesterol regulation contributes to intracrine androgen production during progression to CRPC.

Mice bearing LNCaP tumors had tumors harvested pre-castration (PSA androgen-dependent, AD), 8 days post-castration (PSA nadir, N) and 35 days post-castration (PSA castration resistant, CRPC). Tissue was with frozen or established in culture for ex vivo assay. PSA levels decreased from AD to N, and then increased to CRPC. Total and free cholesterol levels did not change significantly during progression from AD through N to CRPC. Tumor cholesteryl ester levels increased from AD to N then dropped slightly from N to CRPC. The de novo synthesized cholesterol levels decreased from AD to N and then increased at CRPC. The main enzyme responsible for HDL cholesterol influx, SR-B1 increases in expression from N to CRPC. Cholesterol metabolism enzymes increase slightly during progression from AD to N the decrease from N to CRPC. Levels of testosterone significantly decrease from AD to N then increase from N to CRPC by 93.5%. DHT levels increased twofold from AD to CRPC. The DHT levels produced are sufficient for activation of AR in CRPC tumors.

These data show that proteins responsible for cholesterol regulation alter during CaP progression to CRPC. The cellular influx of cholesterol provides precursor for intratumoral steroidogenesis after castration. Also, the data provides evidence that there is increased cholesterol efflux in the CRPC state, so that there is not toxicity to the tumor cells.

Leon CG, Locke JA, Adomat HH, Etinger SL, Twiddy AL, Neumann RD, Nelson CC, Guns ES, Wasan KM

Prostate. 2009 Oct 28;70(4):390-400
doi: 10.1002/pros.21072

UroToday Contributing Editor Christopher P. Evans, MD, FACS

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