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

2016; Impact Journals LLC; Volume: 7; Issue: 29 Linguagem: Inglês

10.18632/oncotarget.9911

1949-2553

Neibla Priego, María Arechederra, Celia Sequera, Paloma Bragado, Ana Vázquez‐Carballo, Álvaro Gutiérrez-Uzquiza, Víctor Martín-Granado, Juan‐José Ventura, Marcelo G. Kazanietz, Carmen Guerrero, Almudena Porrás,

Cell death mechanisms and regulation

// Neibla Priego 1,2,* , María Arechederra 1,2,* , Celia Sequera 1,2 , Paloma Bragado 3 , Ana Vázquez-Carballo 1,2 , Álvaro Gutiérrez-Uzquiza 1,7 , Víctor Martín-Granado 4 , Juan José Ventura 5 , Marcelo G. Kazanietz 6 , Carmen Guerrero 4 and Almudena Porras 1,2 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.