Blocking HSF1 by dominant-negative mutant to sensitize tumor cells to hyperthermia.
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.
Wang
Jin-Hui
JH
Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, People's Republic of China.
Yao
Ming-Zhong
MZ
Gu
Jin-Fa
JF
Sun
Lan-Ying
LY
Shen
Yu-Fei
YF
Liu
Xin-Yuan
XY
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy / Q000648:ultrastructure; D016923:Cell Death / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use; D005260:Female; D017353:Gene Deletion; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000076249:Heat Shock Transcription Factors; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D009368:Neoplasm Transplantation; D000091402:Prohibitins; D014157:Transcription Factors; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C000717331:PHB2 protein, human; C000717333:Phb2 protein, mouse; D000091402:Prohibitins; D014157:Transcription Factors