title: Overexpression of E-cadherin on melanoma cells inhibits chemokine-promoted invasion involving p190RhoGAP/p120ctn-dependent inactivation of RhoA.
abstract: Melanoma cells express the chemokine receptor CXCR4 that confers high invasiveness upon binding to its ligand CXCL12. Melanoma cells at initial stages of the disease show reduction or loss of E-cadherin expression, but recovery of its expression is frequently found at advanced phases. We overexpressed E-cadherin in the highly invasive BRO lung metastatic cell melanoma cell line to investigate whether it could influence CXCL12-promoted cell invasion. Overexpression of E-cadherin led to defective invasion of melanoma cells across Matrigel and type I collagen in response to CXCL12. A decrease in individual cell migration directionality toward the chemokine and reduced adhesion accounted for the impaired invasion. A p190RhoGAP-dependent inhibition of RhoA activation was responsible for the impairment in chemokine-stimulated E-cadherin melanoma transfectant invasion. Furthermore, we show that p190RhoGAP and p120ctn associated predominantly on the plasma membrane of cells overexpressing E-cadherin, and that E-cadherin-bound p120ctn contributed to RhoA inactivation by favoring p190RhoGAP-RhoA association. These results suggest that melanoma cells at advanced stages of the disease could have reduced metastatic potency in response to chemotactic stimuli compared with cells lacking E-cadherin, and the results indicate that p190RhoGAP is a central molecule controlling melanoma cell invasion.
authors.affiliation: Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biológicas, 28040 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Molina-Ortiz
authors.forename: Rubén A
authors.initials: RA
authors.lastname: Bartolomé
authors.forename: Pablo
authors.initials: P
authors.lastname: Hernández-Varas
authors.forename: Georgina P
authors.initials: GP
authors.lastname: Colo
authors.forename: Joaquin
authors.initials: J
authors.lastname: Teixidó
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000095002:Delta Catenin
chemical_list: C074560:ARHGAP35 protein, human; D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; D020662:Guanine Nucleotide Exchange Factors; D010750:Phosphoproteins; D012097:Repressor Proteins; D020742:rhoA GTP-Binding Protein; D000095002:Delta Catenin; C000722347:CTNND1 protein, human