Despite the substantial benefit of
androgen deprivation
therapy (ADT) for metastatic
prostate cancer, patients often progress to
castration-resistant disease (CRPC) that is more difficult to treat. CRPC is associated with renewed
androgen receptor activity in
tumor cells and restoration of
tumor androgen levels through acquired intratumoral steroidogenesis (AIS). Although
prostate cancer (PCa) cells have been shown to have steroidogenic capability in vitro, we previously found that benign prostate stromal cells (PrSCs) can also synthesize
testosterone (T) from an adrenal precursor,
DHEA, when stimulated with a hedgehog (Hh) pathway agonist, SAG. Here, we show exposure of PrSCs to a different Smoothened (Smo) agonist, Ag1.5, or to
conditioned medium from sonic hedgehog overexpressing LNCaP cells induces steroidogenic
enzyme expression in PrSCs and significantly increases production of T and its precursor
steroids in a Smo-dependent manner from 22-OH-cholesterol substrate. Hh agonist-/
ligand-treated PrSCs produced
androgens at a rate similar to or greater than that of PCa cell lines. Likewise, primary bone marrow stromal cells became more steroidogenic and produced T under the influence of Smo agonist. Treatment of mice bearing LNCaP xenografts with a Smo antagonist,
TAK-441, delayed the onset of CRPC after
castration and substantially reduced
androgen levels in
residual tumors. These outcomes support the idea that stromal cells in ADT-treated primary or metastatic prostate
tumors can contribute to AIS as a consequence of a paracrine Hh signaling microenvironment. As such, Smo antagonists may be useful for targeting prostate
tumor stromal cell-derived AIS and delaying the onset of CRPC after ADT.