Heat shock protein 90: the cancer chaperone
Heat shock protein 90: the cancer chaperone
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DOI：
10.1007/s12038-007-0051-y
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发表时间：
2007-04-01
影响因子：
2.9
通讯作者：
Neckers, Len
中科院分区：
文献类型：
--
作者：
Neckers, Len
热休克蛋白90（Hsp 90）是促进癌细胞生长和/或存活的许多条件活化和/或表达的信号传导蛋白以及多种突变的、嵌合的和/或过表达的信号传导蛋白的稳定性和功能所需的分子伴侣。Hsp 90抑制剂的独特之处在于，尽管它们针对特定的分子靶标，但它们同时抑制多种细胞信号传导途径。通过抑制癌细胞利用的多个重叠生存途径中的节点，Hsp 90抑制剂与标准化疗药物的组合可以显着提高标准药物的体内功效。热休克蛋白90抑制剂可能会绕过特征性的遗传可塑性，使癌细胞最终逃避大多数分子靶向药物的毒性作用。基于机制的Hsp 90抑制剂的使用，无论是单独使用还是与其他药物联合使用，都应该对多种形式的癌症有效。此外，因为Hsp 90抑制剂也诱导Hsp 70的Hsf-1依赖性表达，并且因为某些突变的Hsp 90客户蛋白是神经毒性的，所以这些药物在几种神经变性疾病模型中显示出改善性质，表明Hsp 90抑制剂在治疗涉及神经变性的多种病理中的新作用。
Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signalling proteins, as well as multiple mutated, chimeric, and/or over-expressed signalling proteins, that promote cancer cell growth and/or survival. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple cellular signalling pathways. By inhibiting nodal points in multiple overlapping survival pathways utilized by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should be effective toward multiple forms of cancer. Further, because Hsp90 inhibitors also induce Hsf-1-dependent expression of Hsp70, and because certain mutated Hsp90 client proteins are neurotoxic, these drugs display ameliorative properties in several neurodegenerative disease models, suggesting a novel role for Hsp90 inhibitors in treating multiple pathologies involving neurodegeneration.