title: 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.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Granato
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Chiozzi
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Filardi
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Lavinia Vittoria
authors.initials: LV
authors.lastname: Lotti
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Di Renzo
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy. Electronic address: alberto.faggioni@uniroma1.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Faggioni
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161 Rome, Italy. Electronic address: mara.cirone@uniroma1.it.
authors.forename: Mara
authors.initials: M
authors.lastname: Cirone
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000187:drug effects*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011505:Protein-Tyrosine Kinases
keywords: AG490; Autophagy; HSF1; Mcl-1; PEL; STAT3