Research Papers:
C3G knockdown enhances migration and invasion by increasing Rap1mediated p38α activation while it impairs tumor growth through p38αindependent mechanisms
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Neibla Priego1,2,*, María Arechederra1,2,*, Celia Sequera1,2, Paloma Bragado3, Ana Vázquez-Carballo1,2, Álvaro Gutiérrez-Uzquiza1,7, Víctor Martín-Granado4, Juan José Ventura5, Marcelo G. Kazanietz6, Carmen Guerrero4 and Almudena Porras1,2
1 Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
2 Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
3 Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
4 Centro de Investigación del Cáncer, IBMCC, Departamento de Medicina, Facultad de Medicina, Universidad de Salamanca, Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), Salamanca, Spain
5 Translational Cell and Tissue Research, Department of Imaging and Pathology, Leuven University, Leuven, Belgium
6 Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
7 Present address: Department of Cancer Biology, Biomedical Research Building II/III, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
* These authors have contributed equally to this experimental work
Correspondence to:
Almudena Porras, email:
Carmen Guerrero, email:
Keywords: C3G; p38 MAPK; Rap1; migration; tumorigenesis
Received: December 10, 2015 Accepted: May 25, 2016 Published: June 07, 2016
Abstract
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.