title: β-catenin inhibitor ICAT modulates the invasive motility of melanoma cells.
abstract: Inhibitor of β-catenin and TCF (ICAT) inhibits β-catenin transcriptional activity by competing with T-cell factor/lymphoid enhancer factor. We documented high ICAT levels in human melanoma cells, in which β-catenin signaling is frequently deregulated, finding a correlation with the capacity to form metastases in nude mice. Ectopic expression of ICAT in melanoma cells did not affect their proliferation but increased cell motility and Matrigel invasion of metastatic cells in a manner relying upon stable ICAT-β-catenin interaction. This effect was associated with conversion of an elongated/mesenchymal phenotype to a round/amoeboid phenotype in the absence of similar effects on elongated morphology of nonmetastatic melanoma cells. Transition from mesenchymal to amoeboid movement was associated with decreased levels of NEDD9 and activated Rac1, a positive regulator of mesenchymal movement. Ectopic ICAT promoted colonization of melanoma cells in the lungs of nude mice, suggesting an increase in metastatic potential. Together, our results showed that by downregulating Rac signaling in metastatic melanoma cells, ICAT increased their invasive motility by promoting a morphologic variation that facilitates a favorable adaptation to their microenvironment.
authors: Authors' Affiliations: Institut Curie, Normal and Pathological Development of Melanocytes; CNRS UMR3347; INSERM U1021, Orsay; INSERM IFR54, Institut Gustave-Roussy, Villejuif, France; and Department of Genetics, Louisiana State University Health Sciences Center/Stanley S. Scott Cancer Center, New Orleans, Louisiana.
authors: Mélanie J
authors: MJ
authors: Domingues
authors: Florian
authors: F
authors: Rambow
authors: Bastien
authors: B
authors: Job
authors: Laura
authors: L
authors: Papon
authors: Wanguo
authors: W
authors: Liu
authors: Lionel
authors: L
authors: Larue
authors: Jacky
authors: J
authors: Bonaventure
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008545:Melanoma / Q000401:mortality / Q000473:pathology* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000502:physiology; D051176:beta Catenin / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C411982:CTNNBIP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D051176:beta Catenin