C3G knock-down enhances migration and invasion by increasing Rap1-mediated p38α activation, while it impairs tumor growth through p38α-independent mechanisms

• Published in: Oncotarget Vol. 7; no. 29; pp. 45060 - 45078
• Main Authors: Priego, Neibla, Arechederra, María, Sequera, Celia, Bragado, Paloma, Vázquez-Carballo, Ana, Gutiérrez-Uzquiza, Álvaro, Martín-Granado, Víctor, Ventura, Juan José, Kazanietz, Marcelo G, Guerrero, Carmen, Porras, Almudena
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 19.07.2016
• Subjects: Animals; Carcinogenesis - metabolism; Cell Movement - physiology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Enzyme Activation - physiology; Fibroblasts - metabolism; Gene Knockdown Techniques; Guanine Nucleotide-Releasing Factor 2 - metabolism; HCT116 Cells; Heterografts; Humans; Male; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 14 - metabolism; Neoplasm Invasiveness - pathology; rap1 GTP-Binding Proteins - metabolism; Research Paper; migration; tumorigenesis; p38 MAPK; C3G; Rap1
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.9911

C3G, a Guanine nucleotide Exchange Factor (GEF) for Rap1 and R-Ras, has been shown to play important roles in development and cancer. Previous studies determined that C3G regulates cell death through down-regulation of p38α MAPK activity. Here, we found that C3G knock-down in MEFs and HCT116 cells promotes migration and invasion through Rap1-mediated p38α hyper-activation. These effects of C3G were inhibited by Rap1 knock-down or inactivation. The enhanced migration observed in C3G depleted HCT116 cells was associated with reduction in E-cadherin expression, internalization of ZO-1, actin cytoskeleton reorganization and decreased adhesion. We also found that matrix metalloproteases MMP2 and MMP9 are involved in the pro-invasive effect of C3G down-regulation. Additionally, our studies revealed that both C3G and p38α collaborate to promote growth of HCT116 cells in vitro and in vivo, possibly by enhancing cell survival. In fact, knocking-down C3G or p38α individually or together promoted cell death in vitro, although only the double C3G-p38α silencing was able to increase cell death within tumors. Notably, we found that the pro-tumorigenic function of C3G does not depend on p38α or Rap1 activation. Altogether, our studies uncover novel mechanisms by which C3G controls key aspects of tumorigenesis.