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Blocking HSF1 by dominant-negative mutant to sensitize tumor cells to hyperthermia
Jin-Hui Wang1, Ming-Zhong Yao, Jin-Fa Gu
1Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China.
Abstract:
Heat shock protein 70 (HSP70), an antiapoptotic chaperon protein, is highly expressed in human breast tumors and renders them resistant to such therapy as hyperthermia. In the present study, we inhibited the expression of HSP70 by blocking the heat shock transcription factor 1 (HSF1) function with its dominant-negative mutant (mHSF1) in Bcap37 cells, a thermotolerant breast cancer cell line. Here we report that retrovirus-mediated transfer of mHSF1 led to massive cell death of Bcap37 after hyperthermia. mHSF1 sensitized Bcap37 cells to hyperthermia by promoting apoptosis induced by heat shock. We also examined the efficacy of mHSF1 gene therapy in the nude mouse. mHSF1 transfection led to diminution of tumor growth with hyperthermia therapy. Thus, disrupting HSF1 in combination with hyperthermia may open new possibilities for treatment of cancers that have acquired resistance to heat treatment.
Insights
Inhibiting heat shock protein 70 (HSP70) via heat shock transcription factor 1 (HSF1) disruption enhances hyperthermia cancer therapy. This approach promotes apoptosis and reduces tumor growth in breast cancer models.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Heat shock protein 70 (HSP70) is highly expressed in human breast tumors.
- HSP70 confers resistance to therapies like hyperthermia.
- Targeting HSP70 may overcome treatment resistance.
Purpose of the Study:
- To inhibit HSP70 expression by blocking heat shock transcription factor 1 (HSF1) function.
- To evaluate the efficacy of dominant-negative HSF1 mutant (mHSF1) in sensitizing breast cancer cells to hyperthermia.
- To assess mHSF1 gene therapy combined with hyperthermia in a preclinical cancer model.
Main Methods:
- Utilized retrovirus-mediated transfer of mHSF1 into Bcap37 breast cancer cells.
- Applied hyperthermia treatment to cells and tumor-bearing nude mice.
- Monitored cell death, apoptosis induction, and tumor growth inhibition.
Main Results:
- Retroviral transfer of mHSF1 led to significant Bcap37 cell death post-hyperthermia.
- mHSF1 sensitized Bcap37 cells to hyperthermia by promoting heat-induced apoptosis.
- mHSF1 gene therapy combined with hyperthermia resulted in diminished tumor growth in vivo.
Conclusions:
- Disrupting HSF1 function is a viable strategy to sensitize thermotolerant breast cancer cells to hyperthermia.
- mHSF1 gene therapy in combination with hyperthermia shows promise for treating heat-resistant cancers.
- This combined approach offers a potential new therapeutic avenue for overcoming resistance to heat treatment in cancer.