15-ketoprostaglandin-e2 and Adenocarcinoma-of-Lung

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-α 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-α induced CLDN1 expression in human lung carcinoma A549 cells. Chemical inhibition or siRNA downregulation of Src, PI3K, Akt, MAPKs, NFκB, caspase and PKC demonstrated that PKC, specifically PKCδ, is required for TNF-α 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 PPARγ. Conversely, inhibition of these molecules decreased CLDN1 expression. Additionally, a wound-healing assay demonstrated that TNF-α stimulation, PKC activation, prostaglandin treatment or PPARγ activation enhanced cell migration. In conclusion, TNF-α induced CLDN1 expression is regulated by the PKCδ-iPLA2-PGE2-PPARγ signaling cascade in human lung carcinoma A549 cells.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Caspase 3; Cell Line, Tumor; Cell Movement; Cell Proliferation; Claudin-1; Dinoprostone; Gene Expression Regulation, Neoplastic; Group VI Phospholipases A2; Humans; Lung Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; PPAR gamma; Protein Kinase C-delta; Protein Kinase Inhibitors; RNA, Small Interfering; Signal Transduction; Tumor Necrosis Factor-alpha; Up-Regulation