Triptolide-induced cell death in pancreatic cancer is mediated by O-GlcNAc modification of transcription factor Sp1
Sulagna Banerjee1, Veena Sangwan1, Olivia McGinn1
1Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455.
Abstract:
Pancreatic cancer, the fourth most prevalent cancer-related cause of death in the United States, is a disease with a dismal survival rate of 5% 5 years after diagnosis. One of the survival proteins responsible for its extraordinary ability to evade cell death is HSP70. A naturally derived compound, triptolide, and its water-soluble prodrug, Minnelide, down-regulate the expression of this protein in pancreatic cancer cells, thereby causing cell death. However, the mechanism of action of triptolide has not been elucidated. Our study shows that triptolide-induced down-regulation of HSP70 expression is associated with a decrease in glycosylation of the transcription factor Sp1. We further show that triptolide inhibits glycosylation of Sp1, inhibiting the hexosamine biosynthesis pathway, particularly the enzyme O-GlcNAc transferase. Inhibition of O-GlcNAc transferase prevents nuclear localization of Sp1 and affects its DNA binding activity. This in turn down-regulates prosurvival pathways like NF-κB, leading to inhibition of HSF1 and HSP70 and eventually to cell death. In this study, we evaluated the mechanism by which triptolide affects glycosylation of Sp1, which in turn affects downstream pathways controlling survival of pancreatic cancer cells.
Insights
Triptolide combats pancreatic cancer by inhibiting Sp1 glycosylation, a key survival mechanism. This action disrupts cancer cell survival pathways, leading to cell death.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Pancreatic cancer has a very low survival rate.
- Heat shock protein 70 (HSP70) is a survival protein in pancreatic cancer.
- Triptolide and Minnelide reduce HSP70 expression in pancreatic cancer cells.
Purpose of the Study:
- To elucidate the mechanism of action of triptolide in pancreatic cancer.
- To investigate how triptolide affects HSP70 expression.
- To understand the role of Sp1 glycosylation in pancreatic cancer cell survival.
Main Methods:
- Investigated the effect of triptolide on Sp1 glycosylation.
- Examined the impact of triptolide on the hexosamine biosynthesis pathway and O-GlcNAc transferase.
- Assessed the influence of triptolide on Sp1 nuclear localization and DNA binding.
- Analyzed the downstream effects on prosurvival pathways like NF-κB and HSF1.
Main Results:
- Triptolide down-regulates HSP70 expression by decreasing Sp1 glycosylation.
- Triptolide inhibits the hexosamine biosynthesis pathway, specifically O-GlcNAc transferase.
- Inhibition of O-GlcNAc transferase by triptolide reduces Sp1 nuclear localization and DNA binding.
- Triptolide treatment leads to the downregulation of prosurvival pathways (NF-κB, HSF1) and HSP70, ultimately causing pancreatic cancer cell death.
Conclusions:
- Triptolide's mechanism involves inhibiting Sp1 glycosylation via the O-GlcNAc transferase pathway.
- This inhibition disrupts critical prosurvival pathways, offering a potential therapeutic strategy for pancreatic cancer.
- Understanding this pathway provides new insights into targeting pancreatic cancer cell survival.
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