Presentation Authors: Chengfei Liu, Liangren Liu, Cameron Armstrong*, Joy Yang, Wei Lou, Sacramento, CA, Pui-Kai Li, Clombus, OH, Christopher Evans, Allen Gao, Sacramento, CA
Introduction: Steroid sulfatase (STS) is a key enzyme that catalyzes the hydrolysis of DHEAS to the biologically active DHEA. DHEA is further metabolized to the active androgens that bind the androgen receptor (AR) leading to cell proliferation. STS plays important roles in hormone-responsive malignant growth including prostate cancer. The aim of this study is to determine the role of STS in AR signaling and to explore the potential of targeting STS overcoming castration resistance in prostate cancer.
Methods: Sensitivity of prostate cancer cells to STS inhibitors was tested using cell growth assays and clonogenic assays. Quantitative reverse transcription-PCR, and Western blotting were performed to detect expression levels of STS and AR. Expression of STS was downregulated using siRNA specific to STS. Stable cell lines overexpression of STS were generated and characterized. Steroid profile including DHEA and androgens was analyzed by Liquid Chromatography-Mass Spectrometry (LC-MS). STS activity was determined by 4-Methylumbelliferyl sulfate assay through a fluorescence microtiter plate reader. PSA secretion was determined by ELISA and PSA-luciferase activity was measured by reporter assay. Eleven potent STS inhibitors were synthesized and characterized. Two novel STS inhibitors in vivo efficacy was tested in castration relapsed VCaP xenograft tumor models.
Results: We found STS is overexpressed in CRPC patients and cells. Overexpression of STS in the STS stable expression cells promotes the cellular growth of both LNCaP and C4-2B cells in vitro. Inhibiting STS by siRNA suppresses cell growth and AR signaling. Selected from 11 potential STS inhibitors, two novel small molecule inhibitors (SI-1 and SI-2) inhibit the STS activity and the growth of C4-2B and VCaP cells. SI-1 and SI-2 also significantly suppressed AR transcriptional activity, suggesting that inhibition of STS activity by STS inhibitors downregulates the AR signaling. Additionally, SI-1 and SI-2 significantly suppressed the growth of relapsed VCaP cells and tumors and improved enzalutamide treatment in vitro and in vivo.
Conclusions: STS is involved in castration resistance prostate cancer and inhibition of this enzyme could be a viable strategy to treat CRPC and improve enzalutamide treatment.
Source of Funding: NIH CA179970