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Sensitization of tumor cells to Fas killing through overexpression of heat‐shock transcription factor 1
Author(s) -
Xia Wenle,
Voellmy Richard,
Spector Neil L.
Publication year - 2000
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(200006)183:3<425::aid-jcp16>3.0.co;2-m
Subject(s) - hsf1 , heat shock factor , heat shock protein , heat shock , biology , microbiology and biotechnology , transcription factor , fas ligand , fas receptor , apoptosis , hela , programmed cell death , cancer research , cell , gene , hsp70 , genetics
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. J. Cell. Physiol. 183:425–431, 2000. © 2000 Wiley‐Liss, Inc.