Short circuiting stress protein expression via a tyrosine kinase inhibitor, herbimycin A.

We set out to identify pharmacological means by which to activate the so-called heat shock or stress response and thereby harness the protective effect afforded to the cell by its acquisition of a thermotolerant phenotype. An earlier report by Murakami et al. (1991, Exp. Cell Res., 195: 338-344) described the increased expression of the 70 kDa heat shock proteins in human A431 cells exposed to Herbimycin A (HA), a benzoquinoid ansamycin antibiotic. We show here that treatment of cells with HA results in the increased expression of all of the constitutively expressed stress proteins and confers upon the cells a thermotolerant-like phenotype. Increases in the expression of the stress proteins continued for as long as the cells were exposed to the drug and was independent of the pre-existing levels of the stress proteins. Unlike heat shock or other metabolic stressors, we did not observe any adverse cellular effects following HA exposure. For example, unlike most agents/treatments that elicit the stress response HA-treated cells exhibited no obvious abnormalities with respect to protein maturation, protein insolubility, the integrity of the intermediate filament cytoskeleton, or overall cell viability. In addition, unlike other metabolic stressors, HA treatment did not result in the translocation of hsp 73 into the nucleus/nucleolus. Finally, for at least rodent cells, HA exposure did not result in any obvious activation of the heat shock transcription factor. Based on these findings, we suggest that HA treatment of cells results in a "short-circuiting" of the pathway(s) that normally regulates the expression of the stress proteins. These results are discussed as they pertain to the potential use of HA in animals as a way to harness the protective effects afforded by the stress response.