Triptolide, an Inhibitor of the Human Heat Shock Response That Enhances Stress-induced Cell Death

• Published in: The Journal of biological chemistry Vol. 281; no. 14; pp. 9616 - 9622
• Main Authors: Westerheide, Sandy D., Kawahara, Tiara L.A., Orton, Kai, Morimoto, Richard I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.04.2006; American Society for Biochemistry and Molecular Biology
• Subjects: Antineoplastic Agents - pharmacology; Cell Death - drug effects; Diterpenes - pharmacology; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - drug effects; Epoxy Compounds; Gene Expression Regulation - drug effects; Heat Shock Transcription Factors; HeLa Cells; HSP70 Heat-Shock Proteins - biosynthesis; HSP70 Heat-Shock Proteins - drug effects; Humans; Phenanthrenes - pharmacology; Promoter Regions, Genetic; Transcription Factors - biosynthesis; Transcription Factors - drug effects; Transcriptional Activation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M512044200

Molecular chaperones, inducible by heat shock and a variety of other stresses, have critical roles in protein homeostasis, balancing cell stress with adaptation, survival, and cell death mechanisms. In transformed cells and tumors, chaperones are frequently overexpressed, with constitutive activation of the heat shock transcription factor HSF1 implicated in tumor formation. Here, we describe the activity of triptolide, a diterpene triepoxide from the plant Triptergium wilfordii, as an inhibitor of the human heat shock response. Triptolide treatment of human tissue culture cells prevented the inducible expression of heat shock genes, shown by suppression of an HSP70 promoter-reporter construct and by suppression of endogenous HSP70 gene expression. Upon examining the steps in the HSF1 activation pathway, we found that triptolide abrogates the transactivation function of HSF1 without interfering in the early events of trimer formation, hyperphosphorylation, and DNA binding. The ability of triptolide to inhibit the heat shock response renders these cells sensitive to stress-induced cell death, which may be of great relevance to cancer treatments.