p38 MAP kinase is necessary for melanoma-mediated regulation of VE-cadherin disassembly

• Published in: American Journal of Physiology: Cell Physiology Vol. 298; no. 5; pp. C1140 - C1150
• Main Authors: Khanna, Payal, Yunkunis, Tara, Muddana, Hari S, Peng, Hsin Hsin, August, Avery, Dong, Cheng
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2010
• Subjects: Antigens, CD - genetics; Antigens, CD - metabolism; Biochemistry; Cadherins - genetics; Cadherins - metabolism; Cell culture; Cell Line, Tumor; Cell Movement; Cells; Cytokines - metabolism; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic - physiology; Humans; Kinases; Melanoma - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Proteins; Receptors and Signal Transduction; Skin cancer; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00242.2009

Vascular endothelial (VE)-cadherin is localized to the endothelial borders and the adherens junctions, which are regulated by changes in mitogen-activated protein (MAP) kinases, GTPases, and intracellular calcium. We previously showed that melanoma cells induce VE-cadherin disassembly through contact with human umbilical vein endothelial cells in coculture. However, the exact mechanism by which melanoma cells signal endothelial cells to induce VE-cadherin junction disassembly is not well understood. In this study, VE-cadherin junction disassembly was further examined under fluorescence microscopy. We found that melanoma-induced VE-cadherin junction disassembly and upregulation of p38 MAP kinase in endothelial cells is regulated by both soluble factors from melanomas, particularly interleukin (IL)-8, IL-6, and IL-1beta, and through vascular cell adhesion molecule-1. Neutralizing melanoma-secreted soluble factors reduced endothelial gap formation. Endothelial cells transfected with MAP kinase kinase 6, a direct activator of p38 MAP kinase, increased VE-cadherin-mediated gap formation, facilitating melanoma transendothelial migration. In contrast, endothelial cells transfected with small-interfering RNA against p38 MAP kinase expression largely prevented melanoma transendothelial migration in Boyden chamber experiments. These findings indicate that p38 MAP kinase proteins regulate VE-cadherin junction disassembly, facilitating melanoma migration across endothelial cells.