Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / therapy*
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Cell Line, Tumor
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Death Domain Receptor Signaling Adaptor Proteins / genetics
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Doxycycline / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Knockdown Techniques
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HCT116 Cells
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / metabolism*
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Heat Shock Transcription Factors
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Humans
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Liver Neoplasms / drug therapy
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Liver Neoplasms / genetics
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Liver Neoplasms / therapy*
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Mice
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Molecular Targeted Therapy
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Nuclear Proteins / genetics
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RNA, Small Interfering / genetics
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Xenograft Model Antitumor Assays
Substances
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DEDD2 protein, human
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DNA-Binding Proteins
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Death Domain Receptor Signaling Adaptor Proteins
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HSF1 protein, human
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HSP90 Heat-Shock Proteins
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Heat Shock Transcription Factors
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Hsf1 protein, mouse
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Nuclear Proteins
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RNA, Small Interfering
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Transcription Factors
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Extracellular Signal-Regulated MAP Kinases
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Doxycycline