KU135, a Novel Novobiocin-Derived C-Terminal Inhibitor of the 90-kDa Heat Shock Protein, Exerts Potent Antiproliferative Effects in Human Leukemic Cells
KU135, a Novel Novobiocin-Derived C-Terminal Inhibitor of the 90-kDa Heat Shock Protein, Exerts Potent Antiproliferative Effects in Human Leukemic Cells
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DOI：
10.1124/mol.109.058545
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发表时间：
2009-12-01
影响因子：
3.6
通讯作者：
Robertson, John D.
中科院分区：
文献类型：
--
作者：
Shelton, Shary N.;Shawgo, Mary E.;Robertson, John D.
90kDa热休克蛋白（Hsp90）有助于许多与癌症相关的突变或过表达的信号转导蛋白正确折叠。因此，人们对开发能特异性破坏Hsp90功能的化疗药物有相当大的兴趣。在此，我们研究了一种新型的新生霉素衍生的C末端Hsp90抑制剂（命名为KU135）在Jurkat T淋巴细胞中诱导抗增殖效应的程度。结果表明，KU135直接与Hsp90结合，导致已知的Hsp90客户蛋白降解，并比已有的N末端Hsp90抑制剂17 - 烯丙基氨基 - 去甲氧基格尔德霉素（17 - AAG）诱导出更强的抗增殖效应。对细胞对KU135和17 - AAG反应的进一步研究显示，只有17 - AAG诱导了Hsp70和Hsp90的强烈上调。此外，KU135使野生型细胞发生G₂/M期阻滞，而用17 - AAG处理的细胞则在G₁期积累。而且，发现KU135（而非17 - AAG）是线粒体介导的细胞凋亡的强效诱导剂，部分证据是细胞死亡被Bcl - 2/Bcl - xₗ过表达或凋亡蛋白酶激活因子 - 1（Apaf - 1）的缺失抑制到相似程度。总之，这些数据表明KU135通过调节与17 - AAG所靶向的机制不同的信号通路来抑制细胞增殖，因此为Hsp90抑制提供了新的契机。
The 90-kDa heat shock protein (Hsp90) assists in the proper folding of numerous mutated or overexpressed signal transduction proteins that are involved in cancer. Consequently, there is considerable interest in developing chemotherapeutic drugs that specifically disrupt the function of Hsp90. Here, we investigated the extent to which a novel novobiocin-derived C-terminal Hsp90 inhibitor, designated KU135, induced antiproliferative effects in Jurkat T-lymphocytes. The results indicated that KU135 bound directly to Hsp90, caused the degradation of known Hsp90 client proteins, and induced more potent antiproliferative effects than the established N-terminal Hsp90 inhibitor 17-allylamino-demethoxygeldanamycin (17-AAG). Closer examination of the cellular response to KU135 and 17-AAG revealed that only 17-AAG induced a strong up-regulation of Hsp70 and Hsp90. In addition, KU135 caused wild-type cells to undergo G(2)/M arrest, whereas cells treated with 17-AAG accumulated in G(1). Furthermore, KU135 but not 17-AAG was found to be a potent inducer of mitochondria-mediated apoptosis as evidenced, in part, by the fact that cell death was inhibited to a similar extent by Bcl-2/Bcl-x(L) overexpression or the depletion of apoptotic protease-activating factor-1 (Apaf-1). Together, these data suggest that KU135 inhibits cell proliferation by regulating signaling pathways that are mechanistically different from those targeted by 17-AAG and as such represents a novel opportunity for Hsp90 inhibition.