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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8396205 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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