文章：

针对癌症中的动态HSP90复合体

Targeting the dynamic HSP90 complex in cancer

原文发布日期：2010-08-01

DOI: 10.1038/nrc2887

类型: Review Article

开放获取: 否

要点：

1. Heat shock protein 90 (HSP90) is a molecular chaperone of numerous oncoproteins. Therefore, cancer cells can be considered to be 'addicted' to this molecule.
2. HSP90 is also a mediator of cellular homeostasis. As such, it facilitates numerous transient low-affinity protein–protein interactions that have only recently been identified using bioinformatic and proteomic techniques.
3. Although primarily a cytoplasmic protein, HSP90 affects diverse nuclear processes, including transcription, chromatin remodelling and DNA damage-induced mutation.
4. HSP90 is a conformationally dynamic protein. ATP binding to the amino (N) domain and its subsequent hydrolysis by HSP90 drive a conformational cycle that is essential for chaperone activity.
5. In eukaryotes, co-chaperones and post-translational modifications regulate both client interactions with HSP90 and HSP90 ATPase activity.
6. Co-chaperones and post-translational modifications can also affect the efficacy of HSP90 inhibitors.
7. HSP90 inhibitors currently under clinical evaluation interact with the N domain ATP-binding pocket, prevent ATP binding, and stop the chaperone cycle, leading to client protein degradation.
8. Because of the HSP90 client repertoire, HSP90 inhibitors may combat oncogene switching, which is an important mechanism of tumour escape from tyrosine kinase inhibitors.
9. Derivatives of the coumarin antibiotic novobiocin represent an alternative strategy for inhibiting HSP90 by targeting a unique carboxy-terminal (C) domain.
10. Optimal development of HSP90-directed therapeutics will depend on synthesizing information gained from careful genetic analysis of primary and metastatic tumours with an understanding of the unique environmental context in which the tumour is thriving at the expense of the host.

要点翻译：

1. 热休克蛋白90（HSP90）是多种癌蛋白的分子伴侣。因此，癌细胞可被视为对该分子存在"依赖性"。
2. HSP90亦是细胞稳态的调节介质。通过生物信息学和蛋白质组学技术的最新发现，该蛋白可促进多种瞬时低亲和力的蛋白质相互作用。
3. 虽然HSP90主要是一种胞质蛋白，但它影响多种核内过程，包括转录、染色质重构及DNA损伤诱导的突变。
4. HSP90是一种构象动态蛋白。ATP与其氨基（N）端结构域结合及随后发生的ATP水解，驱动着HSP90构象循环，这对分子伴侣功能至关重要。
5. 在真核生物中，辅伴侣蛋白和翻译后修饰共同调控客户蛋白与HSP90的相互作用及HSP90的ATP酶活性。
6. 辅伴侣蛋白和翻译后修饰也会影响HSP90抑制剂的疗效。
7. 目前处于临床评估阶段的HSP90抑制剂可与N端结构域的ATP结合口袋相互作用，阻止ATP结合并中断分子伴侣循环，从而导致客户蛋白降解。
8. 基于HSP90客户蛋白组的特性，HSP90抑制剂或可对抗癌基因转换——这是肿瘤逃避酪氨酸激酶抑制剂作用的重要机制。
9. 香豆素抗生素新生霉素的衍生物代表了一种靶向独特羧基末端（C）结构域的HSP90抑制新策略。
10. HSP90靶向疗法的最佳开发方案，需综合以下两方面信息：一是通过精细遗传学分析获取的原发性和转移性肿瘤数据，二是对肿瘤以宿主为代价赖以生存的特殊微环境背景的深入理解。

英文摘要：

The molecular chaperone heat shock protein 90 (HSP90) has been used by cancer cells to facilitate the function of numerous oncoproteins, and it can be argued that cancer cells are 'addicted' to HSP90. However, although recent reports of the early clinical efficacy of HSP90 inhibitors are encouraging, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which HSP90 participates in both neoplastic and normal cellular physiology.

摘要翻译： 

分子伴侣热休克蛋白90（HSP90）被癌细胞用来促进多种癌蛋白的功能，可以说癌细胞对HSP90“上瘾”。然而，尽管最近关于HSP90抑制剂早期临床疗效的报道令人鼓舞，但HSP90靶向治疗的最佳应用将取决于对HSP90调控复杂性的理解，以及HSP90在肿瘤和正常细胞生理中参与程度的认识。

原文链接：

Targeting the dynamic HSP90 complex in cancer