Sensitization of tumor cells to fas killing through overexpression of heat-shock transcription factor 1.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Xia, W; Voellmy, R; Spector, NL

Published Date

  • June 2000

Published In

Volume / Issue

  • 183 / 3

Start / End Page

  • 425 - 431

PubMed ID

  • 10797318

Pubmed Central ID

  • 10797318

International Standard Serial Number (ISSN)

  • 0021-9541

Digital Object Identifier (DOI)

  • 10.1002/(SICI)1097-4652(200006)183:3<425::AID-JCP16>3.0.CO;2-M


  • eng

Conference Location

  • United States