文章：

热休克蛋白90和癌症的陪伴

HSP90 and the chaperoning of cancer

原文发布日期：2005-09-20

DOI: 10.1038/nrc1716

类型: Review Article

开放获取: 否

要点：

1. Most heat-shock proteins (HSPs) are constitutively expressed molecular chaperones that guide the normal folding, intracellular disposition and proteolytic turnover of many of the key regulators of cell growth and survival. Their levels of intracellular expression increase in response to protein-denaturing stressors, such as temperature change, as an evolutionarily conserved response to restore the normal protein-folding environment and to enhance cell survival.
2. The essential chaperoning functions of HSPs are subverted during oncogenesis to make malignant transformation possible and to facilitate rapid somatic evolution.
3. Functioning as biochemical buffers for the numerous genetic lesions that are present within tumours, chaperones, especially HSP90, allow mutant proteins to retain or even gain function while permitting cancer cells to tolerate the imbalanced signalling that such oncoproteins create.
4. Highly specific inhibitors of HSP90 have been identified that redirect its chaperoning activity and decrease cellular levels of the many cancer-related client proteins that depend on it for their function.
5. The use of HSP90 inhibitors has proven invaluable at a basic level in probing the complex cellular functions of this chaperone.
6. The modulation of client protein levels has been demonstrated in animal models and cancer patients following systemically well-tolerated exposure to the HSP90 inhibitor 17AAG, which is the first in its class.
7. Work is ongoing to identify and develop new HSP90 inhibitors with improved pharmacological properties.
8. The best way to exploit the novel mechanism of action of HSP90 inhibitors for anticancer therapy remains to be defined, but probably involves combination with conventional cytotoxic drugs or other molecularly targeted agents.

要点翻译：

1. 大多数热休克蛋白（HSPs）是组成性表达的分子伴侣，它们指导细胞生长和存活的关键调控因子的正常折叠、细胞内分布及蛋白水解代谢。面对蛋白质变性应激源（如温度变化）时，其细胞内表达水平会升高，这是进化上保守的应对机制，旨在恢复正常蛋白质折叠环境并增强细胞存活能力。
2. 在肿瘤发生过程中，热休克蛋白的关键伴侣功能被劫持，使得恶性转化成为可能，并促进体细胞的快速进化。
3. 作为肿瘤中大量基因损伤的生物化学缓冲剂，分子伴侣（尤其是HSP90）使突变蛋白能够维持甚至获得功能，同时允许癌细胞耐受此类癌蛋白所产生的不平衡信号传导。
4. 目前已发现HSP90的高特异性抑制剂，可重定向其分子伴侣活性，并降低多种依赖其功能的癌症相关客户蛋白的细胞水平。
5. 基础研究层面证明，HSP90抑制剂在探索该分子伴侣复杂细胞功能方面具有重要价值。
6. 在全身耐受良好的HSP90抑制剂17AAG（该类别首个抑制剂）给药后，动物模型和癌症患者中均观察到客户蛋白水平的调节作用。
7. 目前正在持续研发具有更优药理特性的新型HSP90抑制剂。
8. 利用HSP90抑制剂这一新型作用机制进行抗癌治疗的最佳策略尚待明确，但很可能涉及与传统细胞毒性药物或其他分子靶向药物的联合应用。

英文摘要：

Standing watch over the proteome, molecular chaperones are an ancient and evolutionarily conserved class of proteins that guide the normal folding, intracellular disposition and proteolytic turnover of many of the key regulators of cell growth, differentiation and survival. This essential guardian function is subverted during oncogenesis to allow malignant transformation and to facilitate rapid somatic evolution. Pharmacologically 'bribing' the essential guard duty of the chaperone HSP90 (heat-shock protein of 90 kDa) seems to offer a unique anticancer strategy of considerable promise.

摘要翻译： 

分子伴侣作为蛋白质组的守护者，是一类古老且进化上高度保守的蛋白质，它们指导着许多调控细胞生长、分化和生存的关键蛋白的正常折叠、细胞内定位及蛋白水解降解。在肿瘤发生过程中，这一重要的守护功能被颠覆，从而促进恶性转化并加速体细胞快速进化。药理学上“贿赂”热休克蛋白90（HSP90）这一关键守护者的策略，似乎为抗癌提供了一种极具前景的独特方法。

原文链接：

HSP90 and the chaperoning of cancer