title: Electrophilic prostaglandins and lipid aldehydes repress redox-sensitive transcription factors p53 and hypoxia-inducible factor by impairing the selenoprotein thioredoxin reductase.
abstract: Tumor suppressor p53 exhibits an enigmatic phenotype in cells exposed to electrophilic, cyclopentenone prostaglandins of the A and J series. Namely, cells harboring a wild-type p53 gene accumulate p53 protein that is conformationally and functionally impaired. This occurs via an unknown molecular mechanism. We report that electrophilic cyclopentenone prostaglandins covalently modify and inhibit thioredoxin reductase, a selenoprotein that governs p53 and other redox-sensitive transcription factors. This mechanism accounts fully for the unusual p53 phenotype in cells exposed to electrophilic prostaglandins. Based on this mechanism we derived, tested, and affirmed several predictions regarding the kinetics of p53 inactivation; the protective effects of selenium; the structure-activity relationships for inhibition of thioredoxin reductase and impairment of p53 by electrophilic lipids; the susceptibility of hypoxia-inducible factor to inactivation by electrophilic lipids; and the equivalence of chemical inactivation of p53 to deletion of a p53 allele. Chemical precepts dictate that other electrophilic agents should also inhibit thioredoxin reductase and impair its governance of redox-sensitive proteins. Our results provide a novel framework to understand how endogenous and exogenous electrophiles might participate in carcinogenesis; how selenoproteins and selenium might confer protection against cancer; how certain tumors might acquire their paradoxical p53 phenotype; and how chronic inflammation might heighten the risk for cancer.
authors.affiliation: Huntsman Cancer Institute and Departments of Oncological Science and Medicinal Chemistry, University of Utah, Salt Lake City 84112-5550, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Moos
authors.forename: Kornelia
authors.initials: K
authors.lastname: Edes
authors.forename: Pamela
authors.initials: P
authors.lastname: Cassidy
authors.forename: Edmond
authors.initials: E
authors.lastname: Massuda
authors.forename: F A
authors.initials: FA
authors.lastname: Fitzpatrick
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D017209:Apoptosis; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D011454:Prostaglandins A / Q000494:pharmacology*; D011487:Protein Conformation; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D012097:Repressor Proteins / Q000494:pharmacology; D051140:Selenoproteins; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000502:physiology; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000447:Aldehydes; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D011454:Prostaglandins A; D011506:Proteins; D012097:Repressor Proteins; D051140:Selenoproteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D013880:Thioredoxin-Disulfide Reductase; C027576:4-hydroxy-2-nonenal; C100573:prostaglandin A1