Ouabain-Induced Alterations of the Apical Junctional Complex Involve [alpha]1 and [beta]1 Na,K-ATPase Downregulation and ERK1/2 Activation Independent of Caveolae in Colorectal Cancer Cells

• Published in: The Journal of membrane biology Vol. 247; no. 1; p. 23
• Main Authors: de Souza, Waldemir Fernandes, Barbosa, Leandro Augusto, Liu, Lijun, de Araujo, Wallace Martins, De-freitas-junior, Julio Cesar; Madureira, tunato-miranda, Natalia, Fontes, Carlos Frederico; Leite, Morgado-díaz, José Andrés
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer Nature B.V 01-01-2014
• Subjects: Biomedical research; Cell adhesion & migration; Colorectal cancer; Gene expression; Studies; Brazil
• ISSN: 0022-2631; 1432-1424
• DOI: 10.1007/s00232-013-9607-y

Studies have reported that Na,K-ATPase interacts with E-cadherin to stabilize (AJ) and regulate the expression of claudins, the main proteins present in the tight junction (TJ) in epithelial cells containing caveolae. However, the role of this ATPase in the regulation of the AJ and TJ proteins in colorectal cancer cells as well as the molecular events underlying this event in a caveolae-independent system remain undefined. In the present study, we used ouabain, a classic drug known to inhibit Na,K-ATPase, and Caco-2 cells, which are a well-established human colorectal cancer model that does not exhibit caveolae. We demonstrated that ouabain treatment resulted in a reduction of the [beta]1 Na,K-ATPase protein and cell redistribution of the AJ proteins E-cadherin and [beta]-catenin, as well as the [alpha]1 Na,K-ATPase subunit. Furthermore, ouabain increased claudin-3 protein levels, impaired the TJ barrier function and increased cell viability and proliferation during the early stages of treatment. Additionally, the observed ouabain-induced events were dependent on the activation of ERK1/2 signaling; but in contrast to previous studies, this signaling cascade was caveolae-independent. In conclusion, our findings strongly suggest that [alpha]1 and [beta]1 Na,K-ATPase downregulation and ERK1/2 activation induced by ouabain are interlinked events that play an important role during cell-cell adhesion loss, which is an important step during the tumor progression of colorectal carcinomas.[PUBLICATION ABSTRACT]