MODULATION OF PROSTAGLANDIN A(1) INDUCED THERMOTOLERANCE BY QUERCETININ HUMAN LEUKEMIC-CELLS - ROLE OF HEAT-SHOCK-PROTEIN-70

Prostaglandins of the A type (PGAs) function as signals for heat shock protein (hsp) synthesis in mammalian cells. In human K562 erythroleuk emic cells, PGA(1) induces the synthesis of a M(r) 70,000 hsp (hsp70) by cycloheximide-sensitive activation of heat shock transcription fact or (HSF). Induction of hsp70 has been associated recently with the abi lity of PGA to protect K562 cells From thermal injury, establishing a thermotolerant state; however, the role of hsp70 in thermotolerance is still controversial. Because quercetin was shown to modulate hsp70 ex pression after heat shock in K562 cells, we have investigated the effe ct of this flavonoid on HSF activation, hsp70 synthesis, and thermotol erance in human K562 cells after induction with PGA(1). Quercetin was found to inhibit hsp70 synthesis for a period of 3-6 h after PGA(1) tr eatment. This transient block was exerted at the transcriptional level and was not due to the loss of HSF DNA-binding activity. After the in itial delay, hsp70 synthesis reached the same rate as the PGA(1)-treat ed control, and it was actually prolonged in the presence of quercetin . In PGA(1)-treated cells, quercetin suppressed PGA(1)-induced thermot olerance completely if the heat shock was applied at a time (6 h) when hsp70 synthesis was inhibited, whereas it could not prevent the estab lishment of a thermotolerant state if the heat challenge was applied 2 4 h after treatment, when hsp70 synthesis was not affected. These resu lts support strongly the hypothesis that hsp70 is involved in the esta blishment of thermotolerance in human cells.