Abstract 4760: Oxysterol sulfotransferase interferes with prostate cancer progression

Abstract Background: Oxysterol sulfotransferase (SULT2B) mediates enzymatic sulfation of oxysterols. Oxysterols are agonist ligands for the nuclear receptor LXR (liver X receptor) and upon sulfation they become LXR inert. Poor overall survival is linked to low-SULT2B tumors in primary PC (TCGA data) and in esophageal carcinoma, evident for post-surgery patients1. We have shown that clinical samples of metastatic castration-resistant prostate cancer (CRPC) lack SULT2B, and it is reduced or undetectable for a subset of primary PC. In a CRPC model, SULT2B ablation led to faster xenograft growth; increased cell migration and invasion; EMT-like activation; upregulation of AKR1C3, which is a key enzyme for androgen biosynthesis; and activation of ERK - a kinase that regulates cell survival2. LXR is inactivated in SULT2B-overexpressed cells3, and we observed AKR1C3 upregulation in LXRα-silenced cells. Herein we report impacts of high SULT2B on CRPC cells in culture and xenografts. Results: PC3 cells, transduced to express SULT2B and Akaluciferase reporter (PC3-SA cells) or reporter only (PC3-VA cells) were isolated under antibiotic selection and flow sorted to >98% enrichment for the transduced genes on the basis of fluorescence from the Venus fluorescent protein. PC3-VA and PC3-SA cells showed similar proliferation rates in vitro. In contrast, the growth of PC3-SA xenografts showed marked and statistically significant reduction compared to PC3-VA xenografts. The reduction was calculated from differences in tumor volumes and tumor-emitted luminescence. Apoptosis, evident from caspase3 cleavage, was detected in the SA, not VA xenografts. Cleaved caspase3 in tumors was detected by Western Blot and IHC analyses. Xenograft growth was also reduced for SULT2B-high tumors of castration-resistant CWR22Rv cells which, unlike PC3 cells, express androgen receptor. The inhibition of SULT2B-high tumors is consistent with our earlier data showing escalated growth of SULT2B-null xenografts. Further, SULT2B-expressing CRPC cells showed enhanced sensitivity to an anti-cancer biologic for the inhibition of cell proliferation and invasion in vitro. Bioinformatic probing of single cell RNA sequences is ongoing to identify genes expressed differentially and pathways impacted in response to SULT2B expression. Conclusion: SULT2B interferes with CRPC xenograft growth and causes enhanced sensitization of CRPC cells to an anti-cancer biologic. Factors extrinsic to cancer cells are likely to play a role in the growth suppression of high-SULT2B tumors to account for the result showing a lack of impact of SULT2B on cell proliferation in vitro. Our study of allograft tumors in syngeneic mice may identify extrinsic factor(s) at the tumor niche that are involved in the growth suppression of SULT2B-positive prostate tumors. Funding: DoD-W81XWH-21-1-0307 & NIH-R21CA289167 Refs (PMID): 1) 34730281; 2) 94239; 3) 17189208 Citation Format: Bobae Park, Okunola Igbekoyi, Mukund Bhandari, Bandana Chatterjee. Oxysterol sulfotransferase interferes with prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4760.