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Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells

Oncogene volume 28, pages 2784–2795 (2009)Cite this article

Abstract

Signal transducer and activator of transcription 3 (Stat3) is the major mediator of interleukin-6 (IL-6) family cytokines. In addition, Stat3 is known to be involved in the pathophysiology of many malignancies. Here, we show that the cis-trans peptidyl-prolyl isomerase cyclophilin (Cyp) B specifically interacts with Stat3, whereas the highly related CypA does not. CypB knockdown inhibited the IL-6-induced transactivation potential but not the tyrosine phosphorylation of Stat3. Binding of CypB to Stat3 target promoters and alteration of the intranuclear localization of Stat3 on CypB depletion suggested a nuclear function of Stat3/CypB interaction. By contrast, CypA knockdown inhibited Stat3 IL-6-induced tyrosine phosphorylation and nuclear translocation. The Cyp inhibitor cyclosporine A (CsA) caused similar effects. However, Stat1 activation in response to IL-6 or interferon-γ was not affected by Cyp silencing or CsA treatment. As a result, Cyp knockdown shifted IL-6 signaling to a Stat1-dominated pathway. Furthermore, Cyp depletion or treatment with CsA induced apoptosis in IL-6-dependent multiple myeloma cells, whereas an IL-6-independent line was not affected. Thus, Cyps support the anti-apoptotic action of Stat3. Taken together, CypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. These data also suggest a novel mechanism of CsA action.

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Acknowledgements

We thank Hans-Georg Kräusslich, University Heidelberg, Germany, and Stefan Rose-John, University Kiel, Germany, for CypA vector and recombinant IL-6, respectively. INA-6 cells were kindly provided by Renate Burger and Martin Gramatzki, University Kiel, Germany. This work was supported by SFB610 (project C2) from the Deutsche Forschungsgemeinschaft.

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Author notes

  1. K Bauer and A K Kretzschmar: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Clinical Immunology and Transfusion Medicine, Medical Faculty, University of Leipzig, Leipzig, Germany

    K Bauer, A K Kretzschmar, H Cvijic, C Blumert, D Löffler, K Brocke-Heidrich & F Horn

  2. Interdisciplinary Center for Clinical Research, University of Leipzig, Leipzig, Germany

    K Bauer, D Löffler, K Brocke-Heidrich & F Horn

  3. Max Planck Research Unit for Enzymology of Protein Folding, Halle (Saale), Germany

    C Schiene-Fischer & G Fischer

  4. Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

    A Sinz

  5. Department of Pathology, Northwestern University, Chicago, IL, USA

    C V Clevenger

  6. Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany

    A K Kretzschmar & F Horn

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Correspondence to F Horn.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Bauer, K., Kretzschmar, A., Cvijic, H. et al. Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells. Oncogene 28, 2784–2795 (2009). https://doi.org/10.1038/onc.2009.142

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