Chen Yaoyu, Chen Jinyun, Loo Alice, Jaeger Savina, Bagdasarian Linda, Yu Jianjun, Chung Franklin, Korn Joshua, Ruddy David, Guo Ribo, McLaughlin Margaret E, Feng Fei, Zhu Ping, Stegmeier Frank, Pagliarini Raymond, Porter Dale, Zhou Wenlai
Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
Oncotarget. 2013 Jun;4(6):816-29. doi: 10.18632/oncotarget.991.
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.
分子伴侣热休克蛋白90（HSP90）促进多种致癌蛋白的正确折叠，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点，但HSP90抑制剂的疗效可能会受到HSP90抑制诱导的反馈机制的限制。通过汇集RNA干扰筛选，我们发现热休克因子1（HSF1）是HSP90抑制剂的增敏剂。在各种癌细胞系和肿瘤小鼠模型中，当HSF1基因敲低与HSP90抑制剂联合处理时，观察到显著的联合效应。有趣的是，HSF1在肝细胞癌（HCC）患者样本中高表达，且HCC对联合治疗敏感，这表明联合治疗具有潜在的应用前景。为了了解联合效应的机制，我们发现HSF1的一个靶基因DEDD2参与减弱HSP90抑制剂的作用。因此，HSP90抑制剂诱导的HSF1转录活性提供了一种限制HSP90抑制剂活性的反馈机制，而靶向HSF1可能为增强HSP90抑制剂在人类癌症中的活性提供一条新途径。
