Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells

Abstract

PEL cells relay on the constitutive activation of STAT3 for their survival, thus its inhibition by AG490 leads to apoptotic cell death. In this study, we found that the cytotoxic activity of AG490 correlated with the reduction of HSP70 and its master regulator HSF1 that, based on knocking-down experiments, was found to play a pro-survival role in PEL cells. To counteract the pro-death effect mediated by HSF1/HSP70 down-regulation, AG490 induced a complete autophagy, whose inhibition potentiated its cytotoxic effect against PEL cells. AG490 as well as HSF1 siRNA reduced the expression of Mcl-1, a Bcl-2 family member that negatively regulates apoptosis and autophagy. These results suggest that STAT3 inhibition, by down-regulating the expression of HSF1/HSP70, reduces Mcl-1 and leads to both apoptosis and autophagy induction in PEL cells.