Abstract
Background:
Preclinical evaluation of triptolide shows pancreatic tumor regression in animal models.
Results:
Triptolide deregulates glycosylation of Sp1, leading to its decreased activity and causing pancreatic cancer cell death associated with down-regulating HSP70.
Conclusion:
Triptolide down-regulation of HSP70 is associated with inhibition of Sp1 activity in pancreatic cancer.
Significance:
This mechanism is of relevance, as its water-soluble prodrug, Minnelide, is currently under Phase 1 clinical trial.
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.
