The development of castration-resistant prostate cancer (CRPC) is
associated with the activation of intratumoral androgen biosynthesis and
an increase in androgen receptor (AR) expression. We recently
demonstrated that, similarly to the clinical CRPC, orthotopically grown
castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR
and retain intratumoral androgen concentrations similar to tumors grown
in intact mice. Herein, we show that antiandrogen treatment
(enzalutamide or ARN-509) significantly reduced (10-fold, P < 0.01)
intratumoral testosterone and dihydrotestosterone concentrations in the
CR-VCaP tumors, indicating that the reduction in intratumoral androgens
is a novel mechanism by which antiandrogens mediate their effects in
CRPC. Antiandrogen treatment also altered the expression of multiple
enzymes potentially involved in steroid metabolism. Identical to
clinical CRPC, the expression levels of the full-length AR (twofold,
P < 0.05) and the AR splice variants 1 (threefold, P < 0.05) and 7
(threefold, P < 0.01) were further increased in the
antiandrogen-treated tumors. Nonsignificant effects were observed in the
expression of certain classic androgen-regulated genes, such as TMPRSS2
and KLK3, despite the low levels of testosterone and
dihydrotestosterone. However, other genes recently identified to be
highly sensitive to androgen-regulated AR action, such as NOV and
ST6GalNAc1, were markedly altered, which indicated reduced androgen
action. Taken together, the data indicate that, besides blocking AR,
antiandrogens modify androgen signaling in CR-VCaP xenografts at
multiple levels.