Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule.
Stress response pathways allow cells to sense and respond to environmental changes and adverse pathophysiological states. Pharmacological modulation of cellular stress pathways has implications in the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. The quinone methide triterpene celastrol, derived from a traditional Chinese medicinal herb, has numerous pharmacological properties, and it is a potent activator of the mammalian heat shock transcription factor HSF1. However, its mode of action and spectrum of cellular targets are poorly understood. We show here that celastrol activates Hsf1 in Saccharomyces cerevisiae at a similar effective concentration seen in mammalian cells. Transcriptional profiling revealed that celastrol treatment induces a battery of oxidant defense genes in addition to heat shock genes. Celastrol activated the yeast Yap1 oxidant defense transcription factor via the carboxy-terminal redox center that responds to electrophilic compounds. Antioxidant response genes were likewise induced in mammalian cells, demonstrating that the activation of two major cell stress pathways by celastrol is conserved. We report that celastrol's biological effects, including inhibition of glucocorticoid receptor activity, can be blocked by the addition of excess free thiol, suggesting a chemical mechanism for biological activity based on modification of key reactive thiols by this natural product.
Trott
Amy
A
Department of Microbiology and Molecular Genetics, University of Texas Medical School, Houston, TX 77030, USA.
West
James D
JD
Klaić
Lada
L
Westerheide
Sandy D
SD
Silverman
Richard B
RB
Morimoto
Richard I
RI
Morano
Kevin A
KA
D000222:Adaptation, Physiological / Q000187:drug effects; D000975:Antioxidants / Q000378:metabolism*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D016877:Oxidants / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013696:Temperature; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
D000975:Antioxidants; D001688:Biological Products; D004268:DNA-Binding Proteins; C067168:HSF1 protein, S cerevisiae; D006360:Heat-Shock Proteins; D016877:Oxidants; D053978:Pentacyclic Triterpenes; D029701:Saccharomyces cerevisiae Proteins; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; D014315:Triterpenes; C086677:YAP1 protein, S cerevisiae; C050414:celastrol