Abstract 1917: Loss of steroid sulfotransferase (SULT) in human prostate cancer: Potential implications for SULT as a biomarker and therapeutic target.

Abstract

Abstract Purpose: Reactivated androgen receptor, fueled by elevated tumor tissue 5α-dihydrotestosterone (DHT), plays a key role in the reemergence of prostate cancer. Primary prostate cancer almost always regresses in response to androgen deprivation therapy. The disease, however, recurs and progresses to therapy resistance and death in ∼30% patients. New-generation drugs that inhibit androgen receptor (MDV3100™) or enzymes involved in androgen biosynthesis (Zytiga™, TAK-700™, Dutasteride™) extend survival of post-chemotherapy patients for a limited period following which therapy resistance emerges– hence the challenge to develop alternate means for reducing intra-tumor androgen signaling. Design and Results: 3β-sulfation of dehydroepiandrosterone (DHEA), mediated by the prostate-expressed sulfotransferase SULT2B1b (hereon SULT), is likely to reduce intra-prostate androgen levels since sulfated DHEA cannot be converted to androstenedione and thus to testosterone and DHT. We tested whether enzyme-catalyzed sulfation of DHEA, the obligate precursor steroid for androgen synthesis, is targetable to inhibit prostate cancer. Results show that SULT silencing increased prostate cancer cell proliferation. Clinical prostate cancer specimens showed markedly reduced SULT expression, revealed by immunohistochemistry, western blotting and mRNA quantification. 1,25-dihydroxy vitamin D3 (D3) and sterols enhanced SULT expression due to induction of the SULT2B-encoding gene by D3-activated vitamin D receptor (VDR) and sterol-activated liver X receptor (LXRα). Conclusion: Tumor SULT levels may be a marker for predicting prostate cancer recurrence and progression. We also anticipate that enhancement of SULT activity in tumors by activating VDR and LXRα through combined therapeutic intervention with D3 and sterols would limit the tumor androgen pool and inhibit recurrent, therapy-resistant prostate cancer. Citation Format: Nooshin Mirkheshti, Chung S. Song, Bandana Chatterjee. Loss of steroid sulfotransferase (SULT) in human prostate cancer: Potential implications for SULT as a biomarker and therapeutic target. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1917. doi:10.1158/1538-7445.AM2013-1917