Hsf1-Mediated Stress Response can Transiently Enhance Cellular Radioresistance

Kabakov, A. E., Malyutina, Y. V. and Latchman, D. S. Hsf1-Mediated Stress Response can Transiently Enhance Cellular Radioresistance. Radiat. Res. 165, 410–423 (2006). To elucidate how the heat-shock transcription factor 1 (Hsf1)-mediated stress response affects cellular radioresistance, mouse embryo fibroblasts with Hsf1-gene knockout (Hsf1−/− cells) or with normal wild-type Hsf1 expression (Hsf1 wild-type cells) were preconditioned by heating (43°C, 30 min) without or with quercetin (an inhibitor of Hsf1) and then exposed to γ radiation (4 or 6 Gy). Some cell samples were infected with virus-based vectors to overexpress the constitutively active (mutant) form of Hsf1 or individual heat-shock proteins (Hsps). The heat preconditioning transiently up-regulated the Hsp levels in Hsf1 wild-type cells and significantly improved their postirradiation survival; these effects could be abolished by quercetin or simulated (without preheating) by the Hsf1 overexpression. In contrast, no enhanced radioresistance was found in heat-preconditioned Hsf1−/− cells that were unable to trigger Hsf1-mediated Hsp induction after heating. However, when the constitutively active Hsf1 was overexpressed in Hsf1−/− cells, the latter accumulated stress-inducible Hsps and became more radioresistant like heat-preconditioned Hsf1 wild-type cells. The overexpression of Hsp70 or/ and Hsp27 also enhanced radioresistance of both cell cultures. Thus the preirradiation stress response resulting in the intracellular Hsp accumulation can improve survival of severely irradiated mammalian cells.