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Published on: March 6, 2018
Cholesterol Sulfotransferase SULT2B1b Modulates Sensitivity to Death Receptor Ligand TNFα in Castration-Resistant
Renee E Vickman1, Jiang Yang1, Nadia A Lanman2
1Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana.
Abstract:
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 TNFα expression in prostate cancer cells and results in NF-κB 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.
Insights
Cholesterol sulfotransferase SULT2B1b enhances prostate cancer cell resistance to TNF-induced apoptosis. Targeting SULT2B1b may improve therapeutic responses in advanced prostate cancer.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Signaling
Background:
- Cholesterol sulfotransferase SULT2B1b influences androgen receptor activity and cell growth.
- The precise mechanisms of SULT2B1b's role in prostate cancer remain unclear.
- The specific advantages conferred by SULT2B1b expression in prostate cancer are not well understood.
Purpose of the Study:
- To elucidate the mechanism by which SULT2B1b affects prostate cancer cells.
- To investigate the role of SULT2B1b in TNF-mediated signaling and apoptosis.
- To determine the clinical relevance of SULT2B1b expression in human prostate cancer.
Main Methods:
- Single-cell mRNA sequencing to compare SULT2B1b knockdown (KD) versus control KD LNCaP cells.
- Analysis of differentially expressed genes and canonical pathways, including death receptor signaling.
- Examination of TNFα expression, NF-κB activation, and TNF-mediated apoptosis.
- Investigation of SULT2B1b overexpression effects and correlation with human prostate cancer patient datasets.
Main Results:
- Over 2,000 differentially expressed genes and altered pathways were identified upon SULT2B1b KD.
- SULT2B1b KD increased TNFα expression and activated NF-κB in a TNF-dependent manner.
- SULT2B1b KD significantly enhanced TNF-mediated apoptosis in both sensitive and resistant prostate cancer cells.
- SULT2B1b overexpression decreased sensitivity to TNF-induced cell death.
- Human prostate cancer data showed an inverse correlation between SULT2B1b expression and TNF-related genes (TNF, CD40LG, FADD, NFKB1).
Conclusions:
- SULT2B1b expression in prostate cancer cells confers resistance to TNF-mediated apoptosis.
- SULT2B1b may provide a growth advantage to prostate cancer cells.
- Targeting SULT2B1b could enhance therapeutic efficacy of TNF treatment in advanced prostate cancer.
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