Hsp90 C-terminal inhibitors exhibit antimigratory activity by disrupting the Hsp90α/Aha1 complex in PC3-MM2 cells.
Hsp90 C-terminal inhibitors exhibit antimigratory activity by disrupting the Hsp90α/Aha1 complex in PC3-MM2 cells.
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DOI：
10.1021/cb5008713
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发表时间：
2015-02-20
影响因子：
4
通讯作者：
Blagg, Brian S. J.
中科院分区：
文献类型：
--
作者：
Ghosh, Suman;Shinogle, Heather E.;Garg, Gaurav;Vielhauer, George A.;Holzbeierlein, Jeffrey M.;Dobrowsky, Rick T.;Blagg, Brian S. J.
人Hsp 90同种型是分子伴侣，其通常在恶性肿瘤中上调，并且代表进行临床评价的Hsp 90抑制剂的主要靶标。热休克蛋白90 α（Hsp 90 α）是一种应激诱导的Hsp 90亚型，在细胞凋亡和肿瘤转移中起重要作用。虽然Hsp 90 α在转移条件下分泌到细胞外空间，但其在癌症生物学中的作用知之甚少。我们报道了Hsp 90 α与Aha 1共伴侣蛋白的结合，发现该复合物定位于分泌囊泡和迁移细胞的前缘。Hsp 90 α的敲低导致细胞迁移缺陷。Hsp 90 α/Aha 1的功能作用通过用各种基于新生霉素的Hsp 90 C-末端抑制剂处理细胞来研究。这些抑制剂破坏了Hsp 90 α/Aha 1复合物，导致Hsp 90 α和Aha 1在细胞质中的重新分布，并减少了细胞迁移。结构-功能研究确定，Hsp 90 α/Aha 1结合的破坏和细胞迁移的抑制与苯甲酰胺侧链的存在相关，因为乙酰胺取代的类似物效果较差。我们的研究结果表明，用新生霉素为基础的Hsp 90 C-末端抑制剂破坏Hsp 90 α/Aha 1相互作用可能会限制肿瘤的转移潜力。
Human Hsp90 isoforms are molecular chaperones that are often up-regulated in malignances and represent a primary target for Hsp90 inhibitors undergoing clinical evaluation. Hsp90α is a stress-inducible isoform of Hsp90 that plays a significant role in apoptosis and metastasis. Though Hsp90α is secreted into the extracellular space under metastatic conditions, its role in cancer biology is poorly understood. We report that Hsp90α associates with the Aha1 co-chaperone and found this complex to localize in secretory vesicles and at the leading edge of migrating cells. Knockdown of Hsp90α resulted in a defect in cell migration. The functional role of Hsp90α/Aha1 was studied by treating the cells with various novobiocin-based Hsp90 C-terminal inhibitors. These inhibitors disrupted the Hsp90α/Aha1 complex, caused a cytoplasmic redistribution of Hsp90α and Aha1, and decreased cell migration. Structure–function studies determined that disruption of Hsp90α/Aha1 association and inhibition of cell migration correlated with the presence of a benzamide side chain, since an acetamide substituted analog was less effective. Our results show that disruption of Hsp90α/Aha1 interactions with novobiocin-based Hsp90 C-terminal inhibitors may limit the metastatic potential of tumors.
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影响因子：
33.6
作者：
Hutagalung AH;Novick PJ
通讯作者：
Novick PJ
DOI：
10.1161/atvbaha.112.256008
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影响因子：
4
作者：
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通讯作者：
Blagg, Brian S. J.