A fraction of patients undergoing
androgen deprivation
therapy (ADT) for advanced
prostate cancer (PCa) will develop recurrent castrate-resistant PCa (CRPC) in bone. Strategies to prevent CRPC relapse in bone are lacking. Here we show that the
cholesterol-lowering drugs
statins decrease
castration-induced bone marrow adiposity in the tumor microenvironment and reduce PCa progression in bone. Using primary bone marrow stromal cells (BMSC) and M2-10B4 cells, we showed that ADT increases bone marrow adiposity by enhancing BMSC-to-adipocyte transition in vitro. Knockdown of
androgen receptor abrogated BMSC-to-adipocyte transition, suggesting an
androgen receptor-dependent event. RNAseq analysis showed that
androgens reduce the secretion of adipocyte
hormones/
cytokines including
leptin during BMSC-to-adipocyte transition. Treatment of PCa C4-2b, C4-2B4, and PC3 cells with
leptin led to an increase in cell cycle progression and nuclear Stat3. RNAseq analysis also showed that
androgens inhibit
cholesterol biosynthesis pathway, raising the possibility that inhibiting
cholesterol biosynthesis may decrease BMSC-to-adipocyte transition. Indeed,
statins decreased BMSC-to-adipocyte transition in vitro and
castration-induced bone marrow adiposity in vivo.
Statin pre-treatment reduced 22RV1 PCa progression in bone after ADT. Our findings with
statin may provide one of the mechanisms to the clinical correlations that
statin use in patients undergoing ADT seems to delay progression to "lethal" PCa.