title: STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis.
abstract: Classical Hodgkin lymphoma (cHL) is a distinct malignancy of the immune system. Despite the progress made in the understanding of the biology of cHL, the transforming events remain to be elucidated. Recently, we demonstrated that the Janus kinase inhibitor AG490 blocked cellular proliferation and STAT3 phosphorylation in cHL. To explore the potential of constitutively activated STAT3 as a drug target and its role in cHL pathogenesis, different cHL cell lines were analyzed. Treatment of cHL cells by the protein tyrosine kinase inhibitor AG17 was associated with inhibition of cellular proliferation and cell cycle arrest. AG17 treatment was accompanied by decreased levels of STAT3 phosphorylation, whereas NF-kappaB and p38/SAPK2 signaling were not inhibited. Incubation with AG17 or AG490 sensitized cHL cells to CD95/Fas/Apo-1 or staurosporine-mediated apoptosis. Coincubation of tyrphostins with staurosporine was accompanied by rapid complete inhibition of STAT3 phosphorylation. RNA interference directed against STAT3 in L428 and L1236 cHL cells demonstrated that STAT3 is essential for cell proliferation of these cHL cells. In conclusion, these findings support the concept that STAT3 signaling is important in the pathogenesis of cHL and tyrphostins are agents for developing new therapeutic strategies.
authors.affiliation: Universität zu Köln, Klinik für Innere Medizin I, Köln, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Holtick
authors.forename: M
authors.initials: M
authors.lastname: Vockerodt
authors.forename: D
authors.initials: D
authors.lastname: Pinkert
authors.forename: N
authors.initials: N
authors.lastname: Schoof
authors.forename: B
authors.initials: B
authors.lastname: Stürzenhofecker
authors.forename: N
authors.initials: N
authors.lastname: Kussebi
authors.forename: K
authors.initials: K
authors.lastname: Lauber
authors.forename: S
authors.initials: S
authors.lastname: Wesselborg
authors.forename: D
authors.initials: D
authors.lastname: Löffler
authors.forename: F
authors.initials: F
authors.lastname: Horn
authors.forename: L
authors.initials: L
authors.lastname: Trümper
authors.forename: D
authors.initials: D
authors.lastname: Kube
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D009570:Nitriles; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D020032:Tyrphostins; D019014:fas Receptor; C001784:SF 6847; D019311:Staurosporine