Although systemic
androgen deprivation prolongs life in advanced
prostate cancer, remissions are temporary because patients almost uniformly progress to a state of a
castration-resistant
prostate cancer (CRPC) as indicated by recurring PSA. This complex process of progression does not seem to be stochastic as the timing and phenotype are highly predictable, including the observation that most
androgen-regulated genes are reactivated despite castrate levels of serum
androgens. Recent evidence indicates that intraprostatic levels of
androgens remain moderately high following systemic
androgen deprivation
therapy, whereas the
androgen receptor (AR) remains functional, and silencing the AR expression following
castration suppresses
tumor growth and blocks the expression of genes known to be regulated by
androgens. From these observations, we hypothesized that CRPC progression is not independent of
androgen-driven activity and that
androgens may be synthesized de novo in CRPC
tumors leading to AR activation. Using the LNCaP xenograft model, we showed that
tumor androgens increase during CRPC progression in correlation to PSA up-regulation. We show here that all
enzymes necessary for
androgen synthesis are expressed in
prostate cancer tumors and some seem to be up-regulated during CRPC progression. Using an ex vivo radiotracing assays coupled to high-performance liquid chromatography-radiometric/mass spectrometry detection, we show that
tumor explants isolated from CRPC progression are capable of de novo conversion of [(14)C]
acetic acid to
dihydrotestosterone and uptake of [(3)H]
progesterone allows detection of the production of six other
steroids upstream of
dihydrotestosterone. This evidence suggests that de novo
androgen synthesis may be a driving mechanism leading to CRPC progression following
castration.