Inhibition of cancer invasion and metastasis by targeting the molecular chaperone heat-shock protein 90.
Inhibition of cancer invasion and metastasis by targeting the molecular chaperone heat-shock protein 90.
复制标题
DOI：
--
复制
发表时间：
2009-03
影响因子：
2
通讯作者：
F. Koga;K. Kihara;L. Neckers
中科院分区：
文献类型：
--
作者：
F. Koga;K. Kihara;L. Neckers
热休克蛋白90（Hsp 90）是一种分子伴侣，是许多决定癌症标志的致癌信号蛋白的稳定性和功能所必需的。受体酪氨酸激酶（RTK）和缺氧诱导因子-1（HIF-1）介导的途径，通常在侵袭性癌症中激活，相互增强，从而有效地促进癌症侵袭和转移。Hsp 90抑制剂通过与单个分子Hsp 90特异性相互作用，导致多种Hsp 90客户蛋白的不稳定和最终降解。这些药物通过同时损害多种Hsp 90依赖性信号传导蛋白，包括HIF-1 α、大多数RTK及其中枢介导物Src、Raf-1和Akt，阻碍参与癌症侵袭和转移的细胞过程。最近，在细胞表面鉴定的一部分Hsp 90已被发现在癌症侵袭和转移中起关键作用。Hsp 90抑制剂，17-烯丙基氨基-17-去甲氧基格尔德霉素，目前正在进行II期临床试验。Hsp 90抑制剂在临床上的潜在效用和问题进行了讨论。对Hsp 90在癌症生物学中的作用的更全面的理解和积累Hsp 90抑制剂的临床数据将指导我们朝着优化这些药物在临床中的使用的目标前进。
Heat-shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of numerous oncogenic signaling proteins that determine the hallmarks of cancer. Receptor tyrosine kinases (RTKs) and hypoxia-inducible factor-1 (HIF-1)-mediated pathways, commonly activated in aggressive cancer, potentiate each other and thus efficiently promote cancer invasion and metastasis. Hsp90 inhibitors, by interacting specifically with a single molecule, Hsp90, cause the destabilization and eventual degradation of multiple Hsp90 client proteins. These agents impede the cellular processes involved in cancer invasion and metastasis by simultaneously impairing multiple Hsp90-dependent signaling proteins including HIF-1alpha, most RTKs and their hub mediators Src, Raf-1 and Akt. Recently, a fraction of Hsp90 identified on the cell surface has been found to play a crucial role in cancer invasion and metastasis. The first-in-class Hsp90 inhibitor, 17-allylamino-17-demethoxy-geldanamycin, is currently in phase II clinical trials. The potential utility and problems of Hsp90 inhibitors in clinical settings are discussed. A fuller understanding of the roles of Hsp90 in cancer biology and accumulating clinical data on Hsp90 inhibitors will guide us toward the goal of optimizing the use of these agents in the clinic.