Endocrine Abstracts

Introduction: Local androgen synthesis in prostate cancer (PC) could contribute to the development of castration-resistant PC (CRPC). Pathways controlling intratumoral steroidogenic enzyme expression in PC are unknown. Since activin has been implicated in regulation of PC growth and steroidogenic enzyme expression in other steroidogenic tissues, we investigated the effect of activin on intratumoral steroidogenesis in PC.

Methods: Activin A effects and regulation of the activin-signaling pathway molecules were investigated in the PC cell lines LNCaP, VCaP and PC3 and in 13 PC xenograft models. Expression levels of activin subunits (INHBA and INHBB) and of the activin antagonist follistatin (FST) were studied in patient PC samples.

Results: Activin A induced the expression of AKR1C3 and HSD17B3, both 17β-hydroxysteroid dehydrogenase enzymes, in LNCaP and VCaP. Activin A also increased the enzyme activity as measured by androstenedione to testosterone conversion. Inhibition of endogenous activin A action in PC3 decreased AKR1C3 and HSD17B3 levels and testosterone synthesis. Androgens suppressed activin A expression in both VCaP cells and xenografts. Anti-proliferative effects of activin A were opposed in the presence of androstenedione. INHBA expression correlated with AKR1C3 levels in patient PC samples. It was increased in CRPC samples and high levels of a ratio the INHBA plus INHBB to FST were associated with a worse metastasis-free survival.

Conclusions: Activin in the prostate is controlled by androgens and regulates local androgen production. Activin antagonism could form a novel therapeutical target in CRPC since activin is a possible intermediate between castration and residual intratumoral androgen levels.