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CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation

CD40 crosslinking plays an important role in regulating cell migration, adhesion and proliferation in renal cell carcinoma (RCC). CD40/CD40L interaction on RCC cells activates different intracellular pathways but the molecular mechanisms leading to cell scattering are not yet clearly defined. Aim of...

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Autores principales: Pontrelli, Paola, Gigante, Margherita, Spadaccino, Federica, Netti, Giuseppe Stefano, Saldarelli, Marilisa, Balducci, Luigi, Gigante, Maddalena, Battaglia, Michele, Storkus, Walter J., Castellano, Giuseppe, Stallone, Giovanni, Gesualdo, Loreto, Ranieri, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396205/
https://www.ncbi.nlm.nih.gov/pubmed/34445576
http://dx.doi.org/10.3390/ijms22168871
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author Pontrelli, Paola
Gigante, Margherita
Spadaccino, Federica
Netti, Giuseppe Stefano
Saldarelli, Marilisa
Balducci, Luigi
Gigante, Maddalena
Battaglia, Michele
Storkus, Walter J.
Castellano, Giuseppe
Stallone, Giovanni
Gesualdo, Loreto
Ranieri, Elena
author_facet Pontrelli, Paola
Gigante, Margherita
Spadaccino, Federica
Netti, Giuseppe Stefano
Saldarelli, Marilisa
Balducci, Luigi
Gigante, Maddalena
Battaglia, Michele
Storkus, Walter J.
Castellano, Giuseppe
Stallone, Giovanni
Gesualdo, Loreto
Ranieri, Elena
author_sort Pontrelli, Paola
collection PubMed
description CD40 crosslinking plays an important role in regulating cell migration, adhesion and proliferation in renal cell carcinoma (RCC). CD40/CD40L interaction on RCC cells activates different intracellular pathways but the molecular mechanisms leading to cell scattering are not yet clearly defined. Aim of our study was to investigate the main intracellular pathways activated by CD40 ligation and their specific involvement in RCC cell migration. CD40 ligation increased the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH (2)-terminal kinase (JNK) and p38 MAPK. Furthermore, CD40 crosslinking activated different transcriptional factors on RCC cell lines: AP-1, NFkB and some members of the Nuclear Factor of Activated T cells (NFAT) family. Interestingly, the specific inhibition of NFAT factors by cyclosporine A, completely blocked RCC cell motility induced by CD40 ligation. In tumor tissue, we observed a higher expression of NFAT factors and in particular an increased activation and nuclear migration of NFATc4 on RCC tumor tissues belonging to patients that developed metastases when compared to those who did not. Moreover, CD40-CD40L interaction induced a cytoskeleton reorganization and increased the expression of integrin β1 on RCC cell lines, and this effect was reversed by cyclosporine A and NFAT inhibition. These data suggest that CD40 ligation induces the activation of different intracellular signaling pathways, in particular the NFATs factors, that could represent a potential therapeutic target in the setting of patients with metastatic RCC.
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spelling pubmed-83962052021-08-28 CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation Pontrelli, Paola Gigante, Margherita Spadaccino, Federica Netti, Giuseppe Stefano Saldarelli, Marilisa Balducci, Luigi Gigante, Maddalena Battaglia, Michele Storkus, Walter J. Castellano, Giuseppe Stallone, Giovanni Gesualdo, Loreto Ranieri, Elena Int J Mol Sci Article CD40 crosslinking plays an important role in regulating cell migration, adhesion and proliferation in renal cell carcinoma (RCC). CD40/CD40L interaction on RCC cells activates different intracellular pathways but the molecular mechanisms leading to cell scattering are not yet clearly defined. Aim of our study was to investigate the main intracellular pathways activated by CD40 ligation and their specific involvement in RCC cell migration. CD40 ligation increased the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH (2)-terminal kinase (JNK) and p38 MAPK. Furthermore, CD40 crosslinking activated different transcriptional factors on RCC cell lines: AP-1, NFkB and some members of the Nuclear Factor of Activated T cells (NFAT) family. Interestingly, the specific inhibition of NFAT factors by cyclosporine A, completely blocked RCC cell motility induced by CD40 ligation. In tumor tissue, we observed a higher expression of NFAT factors and in particular an increased activation and nuclear migration of NFATc4 on RCC tumor tissues belonging to patients that developed metastases when compared to those who did not. Moreover, CD40-CD40L interaction induced a cytoskeleton reorganization and increased the expression of integrin β1 on RCC cell lines, and this effect was reversed by cyclosporine A and NFAT inhibition. These data suggest that CD40 ligation induces the activation of different intracellular signaling pathways, in particular the NFATs factors, that could represent a potential therapeutic target in the setting of patients with metastatic RCC. MDPI 2021-08-18 /pmc/articles/PMC8396205/ /pubmed/34445576 http://dx.doi.org/10.3390/ijms22168871 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pontrelli, Paola
Gigante, Margherita
Spadaccino, Federica
Netti, Giuseppe Stefano
Saldarelli, Marilisa
Balducci, Luigi
Gigante, Maddalena
Battaglia, Michele
Storkus, Walter J.
Castellano, Giuseppe
Stallone, Giovanni
Gesualdo, Loreto
Ranieri, Elena
CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation
title CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation
title_full CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation
title_fullStr CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation
title_full_unstemmed CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation
title_short CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation
title_sort cd40 cross-linking induces migration of renal tumor cell through nuclear factor of activated t cells (nfat) activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396205/
https://www.ncbi.nlm.nih.gov/pubmed/34445576
http://dx.doi.org/10.3390/ijms22168871
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