PMID- 30824526 OWN - NLM STAT- MEDLINE DCOM- 20200501 LR - 20240214 IS - 1557-3125 (Electronic) IS - 1541-7786 (Print) IS - 1541-7786 (Linking) VI - 17 IP - 6 DP - 2019 Jun TI - Cholesterol Sulfotransferase SULT2B1b Modulates Sensitivity to Death Receptor Ligand TNFalpha in Castration-Resistant Prostate Cancer. PG - 1253-1263 LID - 10.1158/1541-7786.MCR-18-1054 [doi] AB - Cholesterol sulfotransferase, SULT2B1b, has been demonstrated to modulate both androgen receptor activity and cell growth properties. However, the mechanism(s) by which SULT2B1b alters these properties within prostate cancer cells has not been described. Furthermore, specific advantages of SULT2B1b expression in prostate cancer cells are not understood. In these studies, single-cell mRNA sequencing was conducted to compare the transcriptomes of SULT2B1b knockdown (KD) versus Control KD LNCaP cells. Over 2,000 differentially expressed genes were identified along with alterations in numerous canonical pathways, including the death receptor signaling pathway. The studies herein demonstrate that SULT2B1b KD increases TNFalpha expression in prostate cancer cells and results in NF-kappaB activation in a TNF-dependent manner. More importantly, SULT2B1b KD significantly enhances TNF-mediated apoptosis in both TNF-sensitive LNCaP cells and TNF-resistant C4-2 cells. Overexpression of SULT2B1b in LNCaP cells also decreases sensitivity to TNF-mediated cell death, suggesting that SULT2B1b modulates pathways dictating the TNF sensitivity capacity of prostate cancer cells. Probing human prostate cancer patient datasets further supports this work by providing evidence that SULT2B1b expression is inversely correlated with TNF-related genes, including TNF, CD40LG, FADD, and NFKB1. Together, these data provide evidence that SULT2B1b expression in prostate cancer cells enhances resistance to TNF and may provide a growth advantage. In addition, targeting SULT2B1b may induce an enhanced therapeutic response to TNF treatment in advanced prostate cancer. IMPLICATIONS: These data suggest that SULT2B1b expression enhances resistance to TNF and may promote prostate cancer. CI - (c)2019 American Association for Cancer Research. FAU - Vickman, Renee E AU - Vickman RE AD - Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana. FAU - Yang, Jiang AU - Yang J AD - Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana. FAU - Lanman, Nadia A AU - Lanman NA AD - Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana. FAU - Cresswell, Gregory M AU - Cresswell GM AD - Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana. FAU - Zheng, Faye AU - Zheng F AD - Department of Statistics, Purdue University, West Lafayette, Indiana. FAU - Zhang, Chi AU - Zhang C AD - Department of Medical and Molecular Genomics, Indiana University, Indianapolis, Indiana. FAU - Doerge, R W AU - Doerge RW AD - Department of Statistics and Data Science; Department of Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania. FAU - Crist, Scott A AU - Crist SA AD - Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana. FAU - Mesecar, Andrew D AU - Mesecar AD AD - Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana. AD - Department of Biochemistry, Purdue University, West Lafayette, Indiana. FAU - Hu, Chang-Deng AU - Hu CD AD - Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana. AD - Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana. FAU - Ratliff, Timothy L AU - Ratliff TL AUID- ORCID: 0000-0003-4221-5416 AD - Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana. tlratliff@purdue.edu. AD - Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana. LA - eng GR - P30 CA023168/CA/NCI NIH HHS/United States GR - P30 CA082709/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20190301 PL - United States TA - Mol Cancer Res JT - Molecular cancer research : MCR JID - 101150042 RN - 0 (CD40LIg fusion protein) RN - 0 (Fas-Associated Death Domain Protein) RN - 0 (NF-kappa B p50 Subunit) RN - 0 (Receptors, Androgen) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.8.2.- (Sulfotransferases) RN - EC 2.8.2.- (cholesterol sulfotransferase) RN - EC 2.8.2.2 (SULT2B1 protein, human) SB - IM MH - Apoptosis/physiology MH - Cell Death/physiology MH - Cell Line, Tumor MH - Fas-Associated Death Domain Protein/metabolism MH - Humans MH - Male MH - NF-kappa B p50 Subunit/metabolism MH - Prostate/metabolism MH - Prostatic Neoplasms, Castration-Resistant/*metabolism MH - Receptors, Androgen/metabolism MH - Recombinant Fusion Proteins/metabolism MH - Signal Transduction/physiology MH - Sulfotransferases/*metabolism MH - Tumor Necrosis Factor-alpha/*metabolism PMC - PMC6548593 MID - NIHMS1523157 COIS- Conflict of Interest Statement: The authors of this manuscript declare no potential conflicts of interest. EDAT- 2019/03/03 06:00 MHDA- 2020/05/02 06:00 PMCR- 2019/12/01 CRDT- 2019/03/03 06:00 PHST- 2018/09/27 00:00 [received] PHST- 2018/12/18 00:00 [revised] PHST- 2019/02/25 00:00 [accepted] PHST- 2019/03/03 06:00 [pubmed] PHST- 2020/05/02 06:00 [medline] PHST- 2019/03/03 06:00 [entrez] PHST- 2019/12/01 00:00 [pmc-release] AID - 1541-7786.MCR-18-1054 [pii] AID - 10.1158/1541-7786.MCR-18-1054 [doi] PST - ppublish SO - Mol Cancer Res. 2019 Jun;17(6):1253-1263. doi: 10.1158/1541-7786.MCR-18-1054. Epub 2019 Mar 1.