Westerheide Sandy D, Kawahara Tiara L A, Orton Kai, Morimoto Richard I
Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, USA.
J Biol Chem. 2006 Apr 7;281(14):9616-22. doi: 10.1074/jbc.M512044200. Epub 2006 Feb 9.
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.
分子伴侣可由热休克及多种其他应激诱导产生，在蛋白质稳态中发挥关键作用，平衡细胞应激与适应、存活及细胞死亡机制。在转化细胞和肿瘤中，分子伴侣常常过度表达，热休克转录因子HSF1的组成型激活与肿瘤形成有关。在此，我们描述了雷公藤内酯醇（一种从植物雷公藤中提取的二萜三环氧化物）作为人类热休克反应抑制剂的活性。用雷公藤内酯醇处理人类组织培养细胞可阻止热休克基因的诱导表达，这通过抑制HSP70启动子 - 报告基因构建体以及抑制内源性HSP70基因表达得以证明。在研究HSF1激活途径中的各个步骤时，我们发现雷公藤内酯醇可消除HSF1的反式激活功能，而不干扰三聚体形成、过度磷酸化和DNA结合等早期事件。雷公藤内酯醇抑制热休克反应的能力使这些细胞对应激诱导的细胞死亡敏感，这可能与癌症治疗密切相关。
