ERK Signaling Pathway Is Constitutively Active in NT2D1 Non-Seminoma Cells and Its Inhibition Impairs Basal and HGF-Activated Cell Proliferation
Luisa Gesualdi,
Marika Berardini,
Bianca Maria Scicchitano,
Clotilde Castaldo,
Mariano Bizzarri,
Antonio Filippini,
Anna Riccioli,
Chiara Schiraldi,
Francesca Ferranti,
Domenico Liguoro,
Rita Mancini,
Giulia Ricci,
Angela Catizone
Affiliations
Luisa Gesualdi
Section of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, “Sapienza” University of Rome, 00161 Rome, Italy
Marika Berardini
Section of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, “Sapienza” University of Rome, 00161 Rome, Italy
Bianca Maria Scicchitano
Section of Histology, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Clotilde Castaldo
Department of Public Health, University of Naples Federico II, 80131 Naples, Italy
Mariano Bizzarri
Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy
Antonio Filippini
Section of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, “Sapienza” University of Rome, 00161 Rome, Italy
Anna Riccioli
Section of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, “Sapienza” University of Rome, 00161 Rome, Italy
Chiara Schiraldi
Department of Experimental Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Francesca Ferranti
Human Spaceflight and Scientific Research Unit, Italian Space Agency, 00133 Roma, Italy
Domenico Liguoro
Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, “Sapienza” University of Rome, 00185 Rome, Italy
Rita Mancini
Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, “Sapienza” University of Rome, 00185 Rome, Italy
Giulia Ricci
Department of Experimental Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Angela Catizone
Section of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, “Sapienza” University of Rome, 00161 Rome, Italy
c-MET/hepatocyte growth factor (HGF) system deregulation is a well-known feature of malignancy in several solid tumors, and for this reason this system and its pathway have been considered as potential targets for therapeutic purposes. In previous manuscripts we reported c-MET/HGF expression and the role in testicular germ cell tumors (TGCTs) derived cell lines. We demonstrated the key role of c-Src and phosphatidylinositol 3-kinase (PI3K)/AKT adaptors in the HGF-dependent malignant behavior of the embryonal carcinoma cell line NT2D1, finding that the inhibition of these onco-adaptor proteins abrogates HGF triggered responses such as proliferation, migration, and invasion. Expanding on these previous studies, herein we investigated the role of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) pathways in the HGF-dependent and HGF-independent NT2D1 cells biological responses. To inhibit MAPK/ERK pathways we chose a pharmacological approach, by using U0126 inhibitor, and we analyzed cell proliferation, collective migration, and chemotaxis. The administration of U0126 together with HGF reverts the HGF-dependent activation of cell proliferation but, surprisingly, does not exert the same effect on NT2D1 cell migration. In addition, we found that the use of U0126 alone significantly promotes the acquisition of NT2D1 «migrating phenotype», while collective migration of NT2D1 cells was stimulated. Notably, the inhibition of ERK activation in the absence of HGF stimulation resulted in the activation of the AKT-mediated pathway, and this let us speculate that the paradoxical effects obtained by using U0126, which are the increase of collective migration and the acquisition of partial epithelium–mesenchyme transition (pEMT), are the result of compensatory pathways activation. These data highlight how the specific response to pathway inhibitors, should be investigated in depth before setting up therapy.
