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.

Abstract

Event Abstract Back to Event 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. Cinzia Fionda1*, Giulia Malgarini1, Alessandra Soriani1, Alessandra Zingoni1, Francesca Cecere1, Marialuisa Iannitto1, Maria Rosaria Ricciardi2, Maria Teresa Petrucci2, Angela Santoni1 and Marco Cippitelli1 1 University of Rome "Sapienza", Department of Molecular Medicine, Italy 2 Sapienza, Department of Ematology, Italy Engagement of NKG2D and DNAM-1 receptors with their ligands 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 human MM (Multiple Myeloma) cells. GSK3 is a 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 is able to up-regulate MICA protein surface, mRNA expression and promoter activity in MM cells without significant effects on the expression of MICB and DNAM-1 ligand PVR/CD155. Moreover, exposure to GSK-3 inhibitors renders myeloma cells more efficient to activate NK cell degranulation and trigger NK cell-mediated cytotoxicity. We could exclude that two transcription factors specifically inhibited by active GSK3, β-catenin or Heat Shock Factor-1 (HSF-1), are involved in the up-regulation of MICA expression by using RNA-interference or viral transduction of constitutive active forms. On the contrary, inhibition of GSK3 correlated with a significant downregulation of STAT3 activation, a negative regulator of MICA transcription. Both Tyr705 phosphorylation and in vivo binding of STAT3 on MICA promoter are reduced by drugs targeting GSK3; 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 mechanism supporting the anti-myeloma activity of GSK3 inhibitors, and suggest their possible immunotherapeutic value. Keywords: NKG2D ligands, ; GSK3, Multiple Myeloma, NK, STAT3 Transcription Factor Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Fionda C, Malgarini G, Soriani A, Zingoni A, Cecere F, Iannitto M, Ricciardi M, Petrucci M, Santoni A and Cippitelli M (2013). 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.. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00214 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Cinzia Fionda, University of Rome "Sapienza", Department of Molecular Medicine, Rome, 00161, Italy, cinzia.fionda@uniroma1.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Cinzia Fionda Giulia Malgarini Alessandra Soriani Alessandra Zingoni Francesca Cecere Marialuisa Iannitto Maria Rosaria Ricciardi Maria Teresa Petrucci Angela Santoni Marco Cippitelli Google Cinzia Fionda Giulia Malgarini Alessandra Soriani Alessandra Zingoni Francesca Cecere Marialuisa Iannitto Maria Rosaria Ricciardi Maria Teresa Petrucci Angela Santoni Marco Cippitelli Google Scholar Cinzia Fionda Giulia Malgarini Alessandra Soriani Alessandra Zingoni Francesca Cecere Marialuisa Iannitto Maria Rosaria Ricciardi Maria Teresa Petrucci Angela Santoni Marco Cippitelli PubMed Cinzia Fionda Giulia Malgarini Alessandra Soriani Alessandra Zingoni Francesca Cecere Marialuisa Iannitto Maria Rosaria Ricciardi Maria Teresa Petrucci Angela Santoni Marco Cippitelli Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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