The therapeutic target Hsp90 and cancer hallmarks.
The therapeutic target Hsp90 and cancer hallmarks.
复制标题
治疗靶标 Hsp90 和癌症标志。
DOI：
10.2174/138161213804143725
复制
发表时间：
2013
影响因子：
3.1
通讯作者：
Neckers L
中科院分区：
文献类型：
--
作者：
Miyata Y;Nakamoto H;Neckers L
热休克蛋白90是一种主要的分子伴侣，在细胞中大量表达，并在帮助其客户蛋白的正确折叠和功能方面起着关键作用。Hsp 90客户蛋白包括多种信号转导分子，如蛋白激酶和类固醇激素受体。癌症是一种复杂的疾病，但大多数类型的人类癌症具有共同的特征，包括生长信号的自给自足，对生长抑制机制不敏感，逃避程序性细胞死亡，无限的复制潜力，持续的血管生成以及组织侵袭和转移。令人惊讶的是，大量的Hsp 90客户蛋白在建立癌细胞标志中起着至关重要的作用。由于Hsp 90在ATP酶循环过程中的构象变化与其功能密切相关，本文首先对Hsp 90的结构和功能进行了综述。许多辅助分子伴侣，包括Hop、p23、Cdc 37、Aha 1和PP 5，通过调节分子伴侣机制与Hsp 90一起工作。热休克蛋白90及其辅助分子伴侣的翻译后修饰对其功能至关重要。许多肿瘤相关的热休克蛋白90客户端蛋白，包括信号激酶，类固醇激素受体，p53和端粒酶，被描述。Hsp 90及其共分子伴侣是这些肿瘤促进客户蛋白的功能所必需的;因此，通过特异性抑制剂如格尔德霉素及其衍生物抑制Hsp 90可减弱肿瘤进展。热休克蛋白90抑制剂是一种潜在的、有效的肿瘤化疗药物，具有独特的特性，并已在临床试验中得到验证。我们描述了可能的机制，为什么热休克蛋白90抑制剂显示选择性癌细胞，即使热休克蛋白90是必不可少的正常细胞。最后，我们讨论了“热休克蛋白90成瘾”的癌细胞，并建议热休克蛋白90在肿瘤的演变中的作用。
Hsp90 is a major molecular chaperone that is expressed abundantly and plays a pivotal role in assisting correct folding and functionality of its client proteins in cells. The Hsp90 client proteins include a wide variety of signal transducing molecules such as protein kinases and steroid hormone receptors. Cancer is a complex disease, but most types of human cancer share common hallmarks, including self-sufficiency in growth signals, insensitivity to growth-inhibitory mechanism, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. A surprisingly large number of Hsp90-client proteins play crucial roles in establishing cancer cell hallmarks. We start the review by describing the structure and function of Hsp90 since conformational changes during the ATPase cycle of Hsp90 are closely related to its function. Many co-chaperones, including Hop, p23, Cdc37, Aha1, and PP5, work together with Hsp90 by modulating the chaperone machinery. Post-translational modifications of Hsp90 and its co-chaperones are vital for their function. Many tumor-related Hsp90-client proteins, including signaling kinases, steroid hormone receptors, p53, and telomerase, are described. Hsp90 and its co-chaperones are required for the function of these tumor-promoting client proteins; therefore, inhibition of Hsp90 by specific inhibitors such as geldanamycin and its derivatives attenuates the tumor progression. Hsp90 inhibitors can be potential and effective cancer chemotherapeutic drugs with a unique profile and have been examined in clinical trials. We describe possible mechanisms why Hsp90 inhibitors show selectivity to cancer cells even though Hsp90 is essential also for normal cells. Finally, we discuss the “Hsp90-addiction” of cancer cells, and suggest a role for Hsp90 in tumor evolution.
登录
查看更多内容
影响因子：
3.5
作者：
Abbas-Terki, T;Donzé, O;Picard, D
通讯作者：
Picard, D
影响因子：
14.9
作者：
Bailey SM;Murnane JP
通讯作者：
Murnane JP
影响因子：
19
作者：
Aoyagi, S;Archer, TK
通讯作者：
Archer, TK
DOI：
10.1073/pnas.0903392106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Caldas-Lopes, Eloisi;Cerchietti, Leandro;Chiosis, Gabriela
通讯作者：
Chiosis, Gabriela
影响因子：
4.8
作者：
Bali, P;Pranpat, M;Bhalla, K
通讯作者：
Bhalla, K