objective: Most prostate cancer patients receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active dehydroepiandrosterone (DHEA) remain in the high range despite anti-androgen treatment. The conversion of DHEAS into DHEA by steroid sulfatase (STS) may contribute to sustained intracrine androgen synthesis. Here, we determine the contribution of STS to treatment resistance and explore the potential of targeting STS to overcome resistance in prostate cancer.
methods: STS expression was examined in patients and cell lines. In vitro, STS activity and expression were modulated using STS specific siRNA or no... More
objective: Most prostate cancer patients receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active dehydroepiandrosterone (DHEA) remain in the high range despite anti-androgen treatment. The conversion of DHEAS into DHEA by steroid sulfatase (STS) may contribute to sustained intracrine androgen synthesis. Here, we determine the contribution of STS to treatment resistance and explore the potential of targeting STS to overcome resistance in prostate cancer.
methods: STS expression was examined in patients and cell lines. In vitro, STS activity and expression were modulated using STS specific siRNA or novel STS inhibitors (STSi). Cell growth, colony formation, androgen production, and gene expression were examined. RNAseq analysis was conducted on VCaP cells treated with STSi. Mice were treated with STSi with or without enzalutamide to determine their effects in vivo.
results: STS is overexpressed in castration resistant prostate cancer (CRPC) patients and resistant cells. STS overexpression increases intracrine androgen synthesis, cell proliferation, and confers resistance to enzalutamide and abiraterone. Inhibition of STS using siRNA suppresses prostate cancer cell growth. Targeting STS activity using STSi inhibits STS activity, suppresses AR transcriptional activity, and reduces the growth of resistant C4-2B and VCaP prostate cancer cells.STSi significantly suppress resistant VCaP tumor growth, decrease serum PSA levels and enhance enzalutamide treatment in vitro and in vivo.
conclusions: These studies suggest that STS drives intracrine androgen synthesis and prostate cancer proliferation. Targeting STS represents a therapeutic strategy to treat CRPC and improve second generation anti-androgen therapy.
