Semaphorin 3c Promotes De Novo Steroidogenesis In Androgen-Deprived Prostate Cancer Cells

Introduction: This project aims to study the biological role of Semaphorin 3C (SEMA3C) in castration resistant prostate cancer (CRPC) progression. We have found that SEMA3C is a key driver of prostate cancer (PCa) growth through activation of epidermal growth factor receptor (EGFR) and cMet receptor tyrosine kinase (RTK) pathways. RTK signalling activation has been shown to induce de novo steroidogenesis, therefore we hypothesize that SEMA3C-mediated RTK signalling may contribute to CRPC progression through promotion of androgen biosynthesis in androgen-deprived PCa cells. Methods: LNCaP and 22Rv1 cells stably overexpressing SEMA3C were compared to mock transfected cells with respect to their in vitro steroidogenesis, secreted hormone levels were measured by Liquid chromatography-mass spectrometry (LC-MS) technique. Also the expression of steroidogenic enzymes and regulatory proteins were tested by quantitative PCR and western blotting. De novo steroidogenesis was detected by pulsing cells with C14-labeled acetate as a steroid precursor; production of intermediates was measured by scintillation. Results: Steroid analysis showed that SEMA3C overexpression can significantly elevate testosterone and dihydrotestosterone secretion by prostate cancer cells. SEMA3C is also able to upregulate STAR, CYP17A1, HSD17β3, AKR1C3 and SRD5A1 expression. Steroid analysis of SEMA3C-overexpressing LNCaP cells incubated with C14-labeled acetate resulted in the increase of the radioisotope-labeled testosterone and pregnenolone. Conclusions: These findings indicate that SEMA3C can promote steroid biosynthesis in androgen deprived prostate cancer cells, thereby SEMA3C signaling pathway can contribute to maintain active AR signaling in CRPC cells. This research line will be followed to measure intratumoral androgen level by inducing subcutaneously xenografted tumors in athymic nude mice. Tumor homogenates’ steroids will then be extracted and run on LC-MS system. Citation Format: Parvin Yenki, Hans Adomat, Chi Wing Cheng, Christopher Ong. Semaphorin 3C promotes de novo steroidogenesis in androgen-deprived prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1164.