Targeting HSF1 sensitizes cancer cells to HSP90 inhibition.
Targeting HSF1 sensitizes cancer cells to HSP90 inhibition.
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DOI：
10.18632/oncotarget.991
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Zhou W
中科院分区：
文献类型：
--
作者：
Chen Y;Chen J;Loo A;Jaeger S;Bagdasarian L;Yu J;Chung F;Korn J;Ruddy D;Guo R;McLaughlin ME;Feng F;Zhu P;Stegmeier F;Pagliarini R;Porter D;Zhou W
分子伴侣热休克蛋白90（HSP 90）促进各种致癌蛋白的适当折叠，并且是某些癌细胞存活所必需的。因此，HSP90是一个有吸引力的药物靶标，但HSP90抑制剂的功效可能受到HSP90抑制诱导的反馈机制的限制。通过混合RNA干扰筛选，我们确定热休克因子1（HSF 1）是热休克蛋白90抑制剂的增敏剂。在多种肿瘤细胞系和肿瘤小鼠模型中，当HSF1敲低加上HSP 90抑制剂治疗时，观察到显著的组合效应。有趣的是，HSF1在肝细胞癌（HCC）患者样本中高度表达，HCC对联合治疗敏感，表明联合治疗的潜在适应症。为了理解联合作用的机制，我们确定了HSF1靶基因DEDD 2参与减弱HSP90抑制剂的作用。因此，HSP90抑制剂诱导的HSF1的转录活性提供了限制HSP90抑制剂活性的反馈机制，并且靶向HSF1可能为增强HSP90抑制剂在人类癌症中的活性提供新的途径。
The molecular chaperone heat shock protein 90 (HSP90) facilitates the appropriate folding of various oncogenic proteins and is necessary for the survival of some cancer cells. HSP90 is therefore an attractive drug target, but the efficacy of HSP90 inhibitor may be limited by HSP90 inhibition induced feedback mechanisms. Through pooled RNA interference screens, we identified that heat shock factor 1(HSF1) is a sensitizer of HSP90 inhibitor. A striking combinational effect was observed when HSF1 knockdown plus with HSP90 inhibitors treatment in various cancer cell lines and tumor mouse models. Interestingly, HSF1 is highly expressed in hepatocellular carcinoma (HCC) patient samples and HCC is sensitive to combinational treatment, indicating a potential indication for the combinational treatment. To understand the mechanism of the combinational effect, we identified that a HSF1-target gene DEDD2 is involved in attenuating the effect of HSP90 inhibitors. Thus, the transcriptional activities of HSF1 induced by HSP90 inhibitors provide a feedback mechanism of limiting the HSP90 inhibitor's activity, and targeting HSF1 may provide a new avenue to enhance HSP90 inhibitors activity in human cancers.
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