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

• Published in: Oncogene Vol. 30; no. 28; pp. 3198 - 3206
• Main Authors: Fagerli, U-M, Ullrich, K, Stühmer, T, Holien, T, Köchert, K, Holt, R U, Bruland, O, Chatterjee, M, Nogai, H, Lenz, G, Shaughnessy, J D, Mathas, S, Sundan, A, Bargou, R C, Dörken, B, Børset, M, Janz, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.07.2011; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/208/2489/68; 692/699/67/1990/804; Apoptosis; Biological and medical sciences; Bone marrow; Bone Marrow Cells - drug effects; Bone Marrow Cells - pathology; Bone tumors; Cell Biology; Cell culture; Cell cycle; Cell growth; Cell Line, Tumor; Cell physiology; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - genetics; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cytokines; Cytokines - metabolism; Cytokines - pharmacology; Development and progression; Down-Regulation - genetics; External stimuli; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic aspects; Glucocorticoids; Growth factors; Human Genetics; Humans; Immediate-Early Proteins - deficiency; Immediate-Early Proteins - genetics; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Interleukin 21; Internal Medicine; Janus kinase; Janus Kinases - metabolism; Kinases; Medical sciences; Medicine; Medicine & Public Health; Microenvironments; Molecular and cellular biology; Molecular genetics; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Oncology; Phosphorylation; Physiological aspects; Plasma cells; Protein kinases; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-serine/threonine kinase; RNA Interference; short-communication; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Stat3 protein; STAT3 Transcription Factor - metabolism; Stromal cells; Transcription factors; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Transcription. Transcription factor. Splicing. Rna processing; Tumor cell lines; Tumor necrosis factor-α; Norway; Germany; multiple myeloma; cytokines; SGK1; STAT3; Immunopathology; Transcription; Enzyme; Growth; Transferases; Cytokine; Malignant hemopathy; Myeloma; Carcinogenesis; Glucocorticoid; Immunoglobulinopathy; Gene; Kinase; Lymphoproliferative syndrome; Serum; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.79

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.