Sensitization of tumor cells to fas killing through overexpression of heat-shock transcription factor 1.
Activation of the heat-shock or stress response is generally considered a cytoprotective response to heat or other proteotoxic stresses. In mammalian cells, stress-induced transcription of heat-shock genes is regulated by heat-shock transcription factor 1 (HSF1). We now show that activation of the Fas death receptor transactivates HSF1 in HeLa cells, a Fas-expressing cervical carcinoma line. Whereas HSF1 is constitutively expressed in a non-DNA-binding, transcriptionally inactive state, activation of Fas leads to enhanced transcription of a heat-shock reporter gene. The effects of Fas on heat-shock-gene transcription do not appear to be a consequence of cell death as they (1) precede apoptotic changes and (2) are not abrogated by YVAD-CMK, an inhibitor of Fas apoptosis that acts by blocking downstream effector proteases. Despite expressing Fas, HeLa cells are relatively insensitive to Fas-mediated killing, indicating that Fas expression alone, although necessary, is not sufficient for apoptosis. By overexpressing a constitutively activated form of HSF1, we sensitize HeLa cells to Fas-mediated killing. These findings shed new light on the interaction between two of the most evolutionarily conserved cell programs in nature, the Fas death pathway and the heat-shock response. Strategies designed to upregulate HSF1 in tumor cells, either through pharmacologic or gene-therapy approaches will hopefully provide a means with which to sensitize tumors to the killing effects of cancer therapies operating through the Fas receptor.
Xia
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Division of Hematology-Oncology, Department of Medicine, University of Miami School of Medicine, Miami, Florida, USA.
Voellmy
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Spector
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D017209:Apoptosis / Q000502:physiology*; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D019014:fas Receptor / Q000502:physiology*
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D019014:fas Receptor; D015500:Chloramphenicol O-Acetyltransferase