Metformin inhibition of colorectal cancer cell migration is associated with rebuilt adherens junctions and FAK downregulation |
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Authors: | Gastón Amable Eduardo Martínez-León María Elisa Picco Sergio I Nemirovsky Enrique Rozengurt Osvaldo Rey |
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Institution: | 1. Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Inmunología, Genética y Metabolismo, Facultad de Farmacia y Bioquímica, Hospital de Clínicas "José de San Martín", Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina;2. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina;3. Department of Medicine, Unit of Signal Transduction and Gastrointestinal Cancer, Division of Digestive Diseases, CURE: Digestive Diseases Research Center and Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California |
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Abstract: | E-cadherin, a central component of the adherens junction (AJ), is a single-pass transmembrane protein that mediates cell–cell adhesion. The loss of E-cadherin surface expression, and therefore cell–cell adhesion, leads to increased cell migration and invasion. Treatment of colorectal cancer (CRC)-derived cells (SW-480 and HT-29) with 2.0 mM metformin promoted a redistribution of cytosolic E-cadherin to de novo formed puncta along the length of the contacting membranes of these cells. Metformin also promoted translocation from the cytosol to the plasma membrane of p120-catenin, another core component of the AJs. Furthermore, E-cadherin and p120-catenin colocalized with β-catenin at cell–cell contacts. Western blot analysis of lysates of CRC-derived cells revealed a substantial metformin-induced increase in the level of p120-catenin as well as E-cadherin phosphorylation on Ser838/840, a modification associated with β-catenin/E-cadherin interaction. These modifications in E-cadherin, p120-catenin and β-catenin localization suggest that metformin induces rebuilding of AJs in CRC-derived cells. Those modifications were accompanied by the inhibition of focal adhesion kinase (FAK), as revealed by a significant decrease in the phosphorylation of FAK at Tyr397 and paxillin at Tyr118. These changes were associated with a reduction in the numbers, but an increase in the size, of focal adhesions and by the inhibition of cell migration. Overall, these observations indicate that metformin targets multiple pathways associated with CRC development and progression. |
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Keywords: | colorectal cancer E-cadherin FAK metformin β-catenin |
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