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Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells

Oncogene volume 30, pages 3198–3206 (2011)Cite this article

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Abstract

Multiple myeloma (MM) is a paradigm for a malignant disease that exploits external stimuli of the microenvironment for growth and survival. A thorough understanding of the complex interactions between malignant plasma cells and their surrounding requires a detailed analysis of the transcriptional response of myeloma cells to environmental signals. We determined the changes in gene expression induced by interleukin (IL)-6, tumor necrosis factor-α, IL-21 or co-culture with bone marrow stromal cells in myeloma cell lines. Among a limited set of genes that were consistently activated in response to growth factors, a prominent transcriptional target of cytokine-induced signaling in myeloma cells was the gene encoding the serine/threonine kinase serum/glucocorticoid-regulated kinase 1 (SGK1), which is a down-stream effector of PI3-kinase. We could demonstrate a rapid, strong and sustained induction of SGK1 in the cell lines INA-6, ANBL-6, IH-1, OH-2 and MM.1S as well as in primary myeloma cells. Pharmacologic inhibition of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway abolished STAT3 phosphorylation and SGK1 induction. In addition, small hairpin RNA (shRNA)-mediated knock-down of STAT3 reduced basal and induced SGK1 levels. Furthermore, downregulation of SGK1 by shRNAs resulted in decreased proliferation of myeloma cell lines and reduced cell numbers. On the molecular level, this was reflected by the induction of cell cycle inhibitory genes, for example, CDKNA1/p21, whereas positively acting factors such as CDK6 and RBL2/p130 were downregulated. Our results indicate that SGK1 is a highly cytokine-responsive gene in myeloma cells promoting their malignant growth.

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Acknowledgements

We thank Brigitte Wollert-Wulf, Mandy Terne, Pia Herrmann (Berlin), Berit Størdal and Hanne Hella (Trondheim) for excellent technical assistance and Hans-Peter Rahn (Berlin) for cell sorting. Reuven Agami (Amsterdam, The Netherlands) kindly provided the pSUPER vector and Matthias Truss (Berlin) the pRepH1 construct. This work was supported by grants from the Deutsche Krebshilfe (10-2225-Ja 1), the Berlin Cancer Society, the Deutsche Forschungsgemeinschaft (KFO 216 to TS, MC and RCB), the Norwegian Cancer Society, the Cancer Fund of St Olavs Hospital, Trondheim, and the Research Council of Norway.

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Authors and Affiliations

  1. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    U-M Fagerli, T Holien, R U Holt, A Sundan & M Børset

  2. Department of Oncology, St Olavs University Hospital, Trondheim, Norway

    U-M Fagerli

  3. Department of Hematology, Oncology and Tumorimmunology, Charité, University Medical School Berlin, Berlin, Germany

    K Ullrich, K Köchert, H Nogai, G Lenz, S Mathas, B Dörken & M Janz

  4. Hematology, Oncology and Tumorimmunology, Max Delbrück Center for Molecular Medicine, Berlin, Germany

    K Ullrich, K Köchert, S Mathas, B Dörken & M Janz

  5. Department of Internal Medicine II and Comprehensive Cancer Center Mainfranken, Division of Hematology, University Hospital Würzburg, Würzburg, Germany

    T Stühmer, M Chatterjee & R C Bargou

  6. Department of Biomedical Science, Faculty of Technology, Sør-Trøndelag University College, Trondheim, Norway

    R U Holt

  7. Center of Medical Genetics and Molecular Medicine, Haukeland University Hospital Bergen, Bergen, Norway

    O Bruland

  8. Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA

    J D Shaughnessy Jr

  9. Department of Immunology and Transfusion Medicine, St Olavs University Hospital, Trondheim, Norway

    M Børset

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  1. U-M Fagerli
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  12. S Mathas
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  15. B Dörken
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Correspondence to M Janz.

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Fagerli, UM., Ullrich, K., Stühmer, T. et al. Serum/glucocorticoid-regulated kinase 1 (SGK1) is a prominent target gene of the transcriptional response to cytokines in multiple myeloma and supports the growth of myeloma cells. Oncogene 30, 3198–3206 (2011). https://doi.org/10.1038/onc.2011.79

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