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Pioglitazone and rosiglitazone decrease prostaglandin E2 in non-small-cell lung cancer cells by up-regulating
Saswati Hazra1, Raj K Batra, Hsin H Tai
1Department of Medicine, Division of Pulmonary, Lung Cancer Research Program and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1690, USA. shazra@mednet.ucla.edu
Molecular Pharmacology
|April 7, 2007
Summary
Thiazolidinediones (TZDs) reduce prostaglandin E2 (PGE2) in lung cancer by increasing its breakdown, not by blocking its production. This PPARgamma-independent mechanism offers a new therapeutic strategy for non-small-cell lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung cancer cells produce prostaglandin E2 (PGE2), an immunosuppressive and antiapoptotic mediator.
- Cyclooxygenase-2 (COX-2) is known to produce PGE2, and peroxisome proliferator-activated receptor (PPAR)gamma ligands like thiazolidinediones (TZDs) inhibit cancer cell growth.
Purpose of the Study:
- To investigate the effect of TZDs (pioglitazone and rosiglitazone) on PGE2 levels in non-small-cell lung cancer (NSCLC) cells.
- To elucidate the mechanism by which TZDs suppress PGE2 production, particularly focusing on COX-2 independent pathways.
Main Methods:
- Treatment of NSCLC A427 and A549 cells with pioglitazone and rosiglitazone.
- Analysis of PGE2 production and expression of prostaglandin synthases and 15-hydroxyprostaglandin dehydrogenase (15-PGDH).
- Utilized small interfering RNA (siRNA) for 15-PGDH and PPARgamma antagonists (dominant-negative PPARgamma, GW9662) to investigate mechanisms.
Main Results:
- Both TZDs significantly inhibited PGE2 production in NSCLC cells through a COX-2 independent pathway.
- TZDs did not down-regulate the expression of key prostaglandin synthases (PGES1, PGES2, cytosolic PGES).
- TZDs induced the expression of 15-PGDH, an enzyme that degrades PGE2, and this induction was crucial for PGE2 suppression. The effect was PPARgamma-independent.
Conclusions:
- Clinically available TZDs can suppress tumor-derived PGE2 in NSCLC by enhancing PGE2 catabolism via 15-PGDH induction.
- This mechanism is independent of PPARgamma activation and COX-2 activity.
- Targeting PGE2 degradation represents a potential therapeutic strategy for lung cancer treatment.
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