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Molecular Targets for Therapy

STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis

Leukemia volume 19, pages 936–944 (2005)Cite this article

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-κB 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.

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Acknowledgements

We are grateful to K Matthias, EM Choi and F von Bonin for technical assistance in some experiments, I Behrmann, E Pfitzner, H Tesch, PC Heinrich and RK Thomas for helpful discussions. This work was supported by grants from the Deutsche Forschungsgemeinschaft within the Sonderforschungsbereich 399 (LT), DFG Ku 954/7-1 (DK), DFG We 1801/1 (SW), the ‘Forschungsförderungsprogramm des Fachbereich Humanmedizin’ of the Georg-August-Universität Göttingen to DK and a fellowship of the ‘Köln Fortune Programm’ of the Universität zu Köln to UH, the German Bundesministerium fuer Bildung und Forschung (Hep-Net; SW), the Landesforschungsschwerpunktprogramm of the Ministry of Science, Research and Arts of the Land Baden-Württemberg (SW), and from the Fortune Program of the University of Tübingen (No. 1250-0-0; KL).

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Author notes

  1. U Holtick and M Vockerodt: These authors contributed equally to this work

Authors and Affiliations

  1. Universität zu Köln, Klinik für Innere Medizin I, Köln, Germany

    U Holtick

  2. Georg-August-Universität Göttingen, Zentrum für Jugend- und Kinderheilkunde, Abteilung Pädiatrie I, Göttingen, Germany

    M Vockerodt

  3. Georg-August-Universität Göttingen, Fachbereich Humanmedizin, Zentrum für Innere Medizin, Abteilung Hämatologie und Onkologie, Göttingen, Germany

    D Pinkert, N Schoof, B Stürzenhofecker, N Kussebi, L Trümper & D Kube

  4. Eberhard-Karls-Universität Tübingen, Abteilung für Innere Medizin I, Tübingen, Germany

    K Lauber & S Wesselborg

  5. Universitätsklinikum Leipzig, Institut für klinische Immunologie und Transfusionsmedizin, Leipzig, Germany

    D Löffler & F Horn

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Correspondence to D Kube.

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Holtick, U., Vockerodt, M., Pinkert, D. et al. STAT3 is essential for Hodgkin lymphoma cell proliferation and is a target of tyrphostin AG17 which confers sensitization for apoptosis. Leukemia 19, 936–944 (2005). https://doi.org/10.1038/sj.leu.2403750

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