Overexpression of E-cadherin on melanoma cells inhibits chemokine-promoted invasion involving p190RhoGAP/p120ctn-dependent inactivation of RhoA.
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.
Molina-Ortiz
Isabel
I
Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biológicas, 28040 Madrid, Spain.
Bartolomé
Rubén A
RA
Hernández-Varas
Pablo
P
Colo
Georgina P
GP
Teixidó
Joaquin
J
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
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