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

Authors :
Giovanni Stallone
Michele Battaglia
Elena Ranieri
Margherita Gigante
Loreto Gesualdo
Federica Spadaccino
Giuseppe Stefano Netti
Maddalena Gigante
Marilisa Saldarelli
Giuseppe Castellano
Walter J. Storkus
Paola Pontrelli
Luigi Balducci
Source :
International Journal of Molecular Sciences, Vol 22, Iss 8871, p 8871 (2021), International Journal of Molecular Sciences, Volume 22, Issue 16
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
16616596 and 14220067
Volume :
22
Issue :
8871
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences
Accession number :
edsair.doi.dedup.....48811df67733b3270ea8992e08888109