Androgen Levels Increase by Intratumoral <i>De novo</i> Steroidogenesis during Progression of Castration-Resistant Prostate Cancer

TLDR

Although androgen‑deprivation therapy extends survival, most patients eventually develop castration‑resistant prostate cancer in which intraprostatic androgen levels and androgen‑regulated genes remain active despite low serum androgens, indicating that AR signaling persists. We hypothesized that CRPC progression depends on de novo intratumoral androgen synthesis that activates AR. Using LNCaP xenografts and ex vivo radiotracing of tumor explants, we demonstrated that intratumoral androgen production rises during CRPC progression and that tumors can convert acetate to dihydrotestosterone and synthesize additional steroids. All enzymes required for androgen synthesis are expressed in prostate tumors, with several upregulated during CRPC, supporting the conclusion that de novo androgen production drives progression after castration.

Abstract

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.