Indomethacin induces cellular morphological change and migration via epithelial-mesenchymal transition in A549 human lung cancer cells: a novel cyclooxygenase-inhibition-independent effect.

Abstract

Levels of cyclooxygenase (COX)-2 and its metabolite prostaglandin E(2) (PGE(2)) are frequently increased in colon cancer and other cancers including lung cancer. Non-steroidal anti-inflammatory drugs are considered to have chemo-preventive effects on these diseases by reducing the biosynthesis of PGE(2) via their inhibition of COX-2. Although the COX-2/PGE(2) pathway may directly impact on lung carcinogenesis, some population-based cohort studies of NSAIDs showed no significant protective effects. In this study, using human non-small-cell lung cancer A549 cells, we examined the effects of indomethacin, a potent NSAID, on the growth and motility of lung cancer cells. Besides inhibiting PGE(2) production and cellular growth, indomethacin caused drastic morphological changes with a loss of stress fibers in a time- and dose-dependent manner. Interestingly, the change in cellular shape caused by indomethacin was not seen when the cells were treated with aspirin or diclofenac, two other NSAIDs, despite the concentrations used being sufficient to inhibit PGE(2) production. The indomethacin-induced morphological changes in A549 cells were accompanied by a reduction in levels of the adhesion molecule E-cadherin and a component of basal lamina, collagen IV, as well as an increase in the activity of a collagenase, matrix metalloprotease-9. Furthermore, indomethacin-induced shape changes resulted in enhanced motility via regulation of peroxisome proliferator-activated receptor γ. The dual effects of indomethacin, inhibition of cellular growth and enhancement of migration, would explain, to some extent, the difficulty in using this NSAID for lung cancer therapy.

• Authors: Tomoko Kato, Hiromichi Fujino, Satomi Oyama, Tatsuo Kawashima, Toshihiko Murayama
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 82 Issue 11 Pg. 1781-91 (Dec 01 2011) ISSN: 1873-2968 [Electronic] England
• PMID: 21840302 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Anticarcinogenic Agents
• Cadherins
• Chromans
• Collagen Type IV
• Cyclooxygenase Inhibitors
• PPAR gamma
• Thiazolidinediones
• Diclofenac
• Cyclooxygenase 2
• PTGS2 protein, human
• Matrix Metalloproteinase 9
• Troglitazone
• Dinoprostone
• Aspirin
• Indomethacin

Topics

• Anticarcinogenic Agents (pharmacology)
• Aspirin (pharmacology)
• Cadherins (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chromans (pharmacology)
• Collagen Type IV (metabolism)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase Inhibitors (pharmacology)
• Diclofenac (pharmacology)
• Dinoprostone (biosynthesis)
• Epithelial-Mesenchymal Transition (drug effects)
• Humans
• Indomethacin (pharmacology)
• Lung Neoplasms
• Matrix Metalloproteinase 9 (metabolism)
• PPAR gamma (agonists)
• Thiazolidinediones (pharmacology)
• Troglitazone