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首页> 外文期刊>Cell cycle >Combined inhibition of Wee1 and Hsp90 activates intrinsic apoptosis in cancer cells
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Combined inhibition of Wee1 and Hsp90 activates intrinsic apoptosis in cancer cells

机译：联合抑制Wee1和Hsp90激活癌细胞的固有凋亡

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摘要

Heat shock protein 90 (Hsp90) is an essential, evolutionarily conserved molecular chaperone. Cancer cells rely on Hsp90 to chaperone mutated and/or activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is frequently cytostatic in nature, and efforts to enhance the antitumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In agreement with previous data obtained using Wee1 siRNA, we show that dual pharmacologic inhibition of Wee1 tyrosine kinase and Hsp90 causes cancer cells to undergo apoptosis in vitro and in vivo. Gene expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional downregulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins, as well as activated Akt, was completely abrogated. These data support the hypothesis that Wee1 inhibition sensitizes cancer cells to Hsp90 inhibitors; they establish combined Wee1/Hsp90 inhibition as a novel therapeutic strategy; and they provide a mechanistic rationale for enhancing the proapoptotic activity of Hsp90 inhibitors.
机译：热激蛋白90（Hsp90）是必需的，进化上保守的分子伴侣。癌细胞依靠Hsp90来伴侣伴侣突变和/或激活的癌蛋白，并且其参与众多信号传导途径使其成为药物开发的有吸引力的靶标。然而，令人惊讶的是，Hsp90抑制剂对癌细胞的影响本质上通常是细胞抑制细胞的作用，并且在临床上努力提高Hsp90抑制剂的抗肿瘤活性仍然是一项重大挑战。与使用Wee1 siRNA获得的先前数据一致，我们表明Wee1酪氨酸激酶和Hsp90的双重药理抑制作用导致癌细胞在体内和体外发生凋亡。基因表达谱分析表明，这种药物组合对内在凋亡途径的诱导与Survivin和Wee1的转录下调相吻合，这在用任何一种试剂单独处理的细胞中均未见到。在翻译水平上，这两种蛋白质以及活化的Akt的表达被完全废除。这些数据支持以下假设：Wee1抑制会使癌细胞对Hsp90抑制剂敏感。他们建立了结合的Wee1 / Hsp90抑制作为一种新的治疗策略。它们为增强Hsp90抑制剂的促凋亡活性提供了机械原理。

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