title: Triptolide-induced cell death in pancreatic cancer is mediated by O-GlcNAc modification of transcription factor Sp1.
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.
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Sulagna
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Veena
authors.initials: V
authors.lastname: Sangwan
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Olivia
authors.initials: O
authors.lastname: McGinn
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Rohit
authors.initials: R
authors.lastname: Chugh
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Vikas
authors.initials: V
authors.lastname: Dudeja
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Selwyn M
authors.initials: SM
authors.lastname: Vickers
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455. Electronic address: asaluja@umn.edu.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Saluja
mesh_terms: D000117:Acetylglucosamine / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004852:Epoxy Compounds / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006031:Glycosylation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010616:Phenanthrenes; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C001899:triptolide; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D000117:Acetylglucosamine
keywords: Heat Shock Protein; Minnelide; O-GlcNAc; Pancreas; Pancreatic Cancer; Sp1; Triptolide