NDLI: Inhibition of glycogen synthase kinase-3 increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of STAT3.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Ricciardi, Maria Rosaria Malgarini, Giulia Cecere, Francesca Cippitelli, Marco Zingoni, Alessandra Federico, Vincenzo Iannitto, Maria Luisa Fionda, Cinzia Soriani, Alessandra Petrucci, Maria Teresa Santoni, Angela
Description	Country affiliation: Italy Author Affiliation: Fionda C ( Department of Molecular Medicine, Cenci Bolognetti Foundation-Pasteur Institute, Sapienza University of Rome, 00161 Rome, Italy.)
Abstract	Engagement of NKG2D and DNAX accessory molecule-1 (DNAM-1) receptors on lymphocytes plays an important role for anticancer response and represents an interesting therapeutic target for pharmacological modulation. In this study, we investigated the effect of inhibitors targeting the glycogen synthase kinase-3 (GSK3) on the expression of NKG2D and DNAM-1 ligands in multiple myeloma (MM) cells. GSK3 is a pleiotropic serine-threonine kinase point of convergence of numerous cell-signaling pathways, able to regulate the proliferation and survival of cancer cells, including MM. We found that inhibition of GSK3 upregulates both MICA protein surface and mRNA expression in MM cells, with little or no effects on the basal expression of the MICB and DNAM-1 ligand poliovirus receptor/CD155. Moreover, exposure to GSK3 inhibitors renders myeloma cells more efficient to activate NK cell degranulation and to enhance the ability of myeloma cells to trigger NK cell-mediated cytotoxicity. We could exclude that increased expression of ß-catenin or activation of the heat shock factor-1 (transcription factors inhibited by active GSK3) is involved in the upregulation of MICA expression, by using RNA interference or viral transduction of constitutive active forms. On the contrary, inhibition of GSK3 correlated with a downregulation of STAT3 activation, a negative regulator of MICA transcription. Both Tyr(705) phosphorylation and binding of STAT3 on MICA promoter are reduced by GSK3 inhibitors; in addition, overexpression of a constitutively active form of STAT3 significantly inhibits MICA upregulation. Thus, we provide evidence that regulation of the NKG2D-ligand MICA expression may represent an additional immune-mediated mechanism supporting the antimyeloma activity of GSK3 inhibitors.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	12
Volume Number	190
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2013-06-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Glycogen Synthase Kinase 3 Immunology Histocompatibility Antigens Class I Killer Cells, Natural Multiple Myeloma Stat3 Transcription Factor Blotting, Western Cell Line, Tumor Chromatin Immunoprecipitation Cytotoxicity, Immunologic Flow Cytometry Fluorescent Antibody Technique Antagonists & Inhibitors Metabolism Lymphocyte Activation Real-time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Transduction, Genetic Transfection Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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