PKCδ-iPLA2-PGE2-PPARγ signaling cascade mediates TNF-α induced Claudin 1 expression in human lung carcinoma cells

Daisuke Iitaka; Serisha Moodley; Hiroki Shimizu; Xiao-Hui Bai; Mingyao Liu

doi:10.1016/j.cellsig.2014.12.015

PKCδ-iPLA2-PGE2-PPARγ signaling cascade mediates TNF-α induced Claudin 1 expression in human lung carcinoma cells

Cell Signal. 2015 Mar;27(3):568-77. doi: 10.1016/j.cellsig.2014.12.015. Epub 2015 Jan 3.

Authors

Daisuke Iitaka¹, Serisha Moodley², Hiroki Shimizu¹, Xiao-Hui Bai³, Mingyao Liu⁴

Affiliations

¹ Latner Thoracic Surgery Research Laboratories, University Health Network Toronto General Research Institute, Toronto, Ontario, Canada; Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
² Latner Thoracic Surgery Research Laboratories, University Health Network Toronto General Research Institute, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
³ Latner Thoracic Surgery Research Laboratories, University Health Network Toronto General Research Institute, Toronto, Ontario, Canada.
⁴ Latner Thoracic Surgery Research Laboratories, University Health Network Toronto General Research Institute, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: mingyao.liu@utoronto.ca.

PMID: 25562426
DOI: 10.1016/j.cellsig.2014.12.015

Abstract

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.

Keywords: Claudin1; Lung cancer; Migration; PKC; TNF pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Caspase 3 / chemistry
Caspase 3 / genetics
Caspase 3 / metabolism
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Claudin-1 / genetics*
Claudin-1 / metabolism*
Dinoprostone / agonists
Dinoprostone / analogs & derivatives
Dinoprostone / metabolism
Dinoprostone / pharmacology
Gene Expression Regulation, Neoplastic / physiology*
Group VI Phospholipases A2 / metabolism
Humans
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
PPAR gamma / agonists
PPAR gamma / metabolism
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase C-delta / antagonists & inhibitors
Protein Kinase C-delta / genetics
Protein Kinase C-delta / metabolism
Protein Kinase Inhibitors / pharmacology
RNA, Small Interfering / metabolism
Signal Transduction* / drug effects
Tumor Necrosis Factor-alpha / agonists
Tumor Necrosis Factor-alpha / metabolism
Tumor Necrosis Factor-alpha / pharmacology*
Up-Regulation / drug effects*

Substances

Claudin-1
PPAR gamma
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
RNA, Small Interfering
Tumor Necrosis Factor-alpha
15-ketoprostaglandin E2
Protein Kinase C-delta
Group VI Phospholipases A2
Caspase 3
Dinoprostone

Abstract

Publication types

MeSH terms

Substances

Grants and funding