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Gambogic acid and gambogenic acid induce a thiol-dependent heat shock response and disrupt the interaction between HSP90 and HSF1 or HSF2
Cell Stress and Chaperones ( IF 3.3 ) Pub Date : 2021-07-30 , DOI: 10.1007/s12192-021-01222-4
Linda Pesonen 1 , Sally Svartsjö 1 , Viktor Bäck 1 , Aurélie de Thonel 2 , Valérie Mezger 2 , Délara Sabéran-Djoneidi 2 , Pia Roos-Mattjus 1
Affiliation  

Cancer cells rely on heat shock proteins (HSPs) for growth and survival. Especially HSP90 has multiple client proteins and plays a critical role in malignant transformation, and therefore different types of HSP90 inhibitors are being developed. The bioactive natural compound gambogic acid (GB) is a prenylated xanthone with antitumor activity, and it has been proposed to function as an HSP90 inhibitor. However, there are contradicting reports whether GB induces a heat shock response (HSR), which is cytoprotective for cancer cells and therefore a potentially problematic feature for an anticancer drug. In this study, we show that GB and a structurally related compound, called gambogenic acid (GBA), induce a robust HSR, in a thiol-dependent manner. Using heat shock factor 1 (HSF1) or HSF2 knockout cells, we show that the GB or GBA-induced HSR is HSF1-dependent. Intriguingly, using closed form ATP-bound HSP90 mutants that can be co-precipitated with HSF1, a known facilitator of cancer, we show that also endogenous HSF2 co-precipitates with HSP90. GB and GBA treatment disrupt the interaction between HSP90 and HSF1 and HSP90 and HSF2. Our study implies that these compounds should be used cautiously if developed for cancer therapies, since GB and its derivative GBA are strong inducers of the HSR, in multiple cell types, by involving the dissociation of a HSP90-HSF1/HSF2 complex.



中文翻译:


藤黄酸和藤黄酸诱导硫醇依赖性热休克反应并破坏 HSP90 与 HSF1 或 HSF2 之间的相互作用



癌细胞依靠热休克蛋白 (HSP) 来生长和存活。特别是HSP90具有多种客户蛋白,在恶性转化中发挥着关键作用,因此不同类型的HSP90抑制剂正在被开发。生物活性天然化合物藤黄酸(GB)是一种具有抗肿瘤活性的异戊二烯化氧杂蒽酮,已被提议作为 HSP90 抑制剂。然而,关于 GB 是否会诱导热休克反应 (HSR) 的报道相互矛盾,热休克反应对癌细胞具有细胞保护作用,因此对于抗癌药物来说是一个潜在的问题特征。在这项研究中,我们证明 GB 和一种结构相关的化合物,称为藤原酸 (GBA),以硫醇依赖性方式诱导强大的 HSR。使用热休克因子 1 ( HSF1 ) 或HSF2敲除细胞,我们发现 GB 或 GBA 诱导的 HSR 是 HSF1 依赖性的。有趣的是,使用可与已知的癌症促进剂 HSF1 共沉淀的封闭形式 ATP 结合的 HSP90 突变体,我们发现内源性 HSF2 也与 HSP90 共沉淀。 GB和GBA处理破坏HSP90和HSF1以及HSP90和HSF2之间的相互作用。我们的研究表明,如果开发用于癌症治疗,应谨慎使用这些化合物,因为 GB 及其衍生物 GBA 通过涉及 HSP90-HSF1/HSF2 复合物的解离,在多种细胞类型中是 HSR 的强诱导剂。

更新日期:2021-08-01
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