Journal
CELLULAR SIGNALLING
Volume 27, Issue 3, Pages 568-577Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2014.12.015
Keywords
Claudin1; TNF pathway; PKC; Migration; Lung cancer
Categories
Funding
- Canadian Institutes of Health Research [MOP-13270, MOP-42546, MOP-119514]
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Claudin 1 (CLDN1) is a critical component of tight junction adhesion complexes that maintains the structural integrity of epithelial cell layers. Dysregulation of CLDN1 is associated with the growth and metastasis of human lung adenocarcinoma. TNF-alpha treatment was previously shown to increase expression of CLDN1 that mediated lung cancer cell morphology changes and migration. This study aimed to elucidate the molecular mechanisms involved in TNF-alpha induced CLDN1 expression in human lung carcinoma A549 cells. Chemical inhibition or siRNA downregulation of Src, PI3K, Akt, MAPKs, NE kappa B, caspase and PKC demonstrated that PKC, specifically PKG5, is required for TNF-alpha induced CLDN1 expression. Further investigation of the PKC pathway revealed that CLDN1 expression is enhanced by the downstream molecules iPLA2, PGE2, 15-keto PGE2 and PPAR gamma. Conversely, inhibition of these molecules decreased CLDN1 expression. Additionally, a wound-healing assay demonstrated that TNF-alpha stimulation, PKC activation, prostaglandin treatment or PPAR gamma activation enhanced cell migration. In conclusion, TNF-alpha induced CLDN1 expression is regulated by the PKC delta-iPLA2-PGE2-PPARy signaling cascade in human lung carcinoma A549 cells. (C) 2015 Elsevier Inc. All rights reserved.
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