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Research ArticleArticle

Pioglitazone and Rosiglitazone Decrease Prostaglandin E2 in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Saswati Hazra, Raj K. Batra, Hsin H. Tai, Sherven Sharma, Xiaoyan Cui and Steven M. Dubinett
Molecular Pharmacology June 2007, 71 (6) 1715-1720; DOI: https://doi.org/10.1124/mol.106.033357
Saswati Hazra
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Raj K. Batra
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Hsin H. Tai
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Sherven Sharma
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Xiaoyan Cui
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Steven M. Dubinett
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Abstract

Lung cancer cells elaborate the immunosuppressive and antiapoptotic mediator prostaglandin E2 (PGE2), a product of cyclooxygenase-2 (COX-2) enzyme activity. Because peroxisome proliferator-activated receptor (PPAR)γ ligands, such as thiazolidinediones (TZDs), inhibit lung cancer cell growth, we examined the effect of the TZDs pioglitazone and rosiglitazone on PGE2 levels in non–small-cell lung cancer (NSCLC) A427 and A549 cells. Both TZDs inhibited PGE2 production in NSCLC cells via a COX-2 independent pathway. To define the mechanism underlying COX-2 independent suppression of PGE2 production, we focused on other enzymes responsible for the synthesis and degradation of PGE2. The expression of none of the three prostaglandin synthases (microsomal PGES1, PGES2 and cystosolic PGES) was down-regulated by the TZDs. It is noteworthy that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that produces biologically inactive 15-ketoprostaglandins from active PGE2, was induced by TZDs. The TZD-mediated suppression of PGE2 concentration was significantly inhibited by small interfering RNA to 15-PGDH. Studies using dominant-negative PPARγ overexpression or 2-chloro-5-nitrobenzanilide (GW9662; a PPARγ antagonist) revealed that the suppressive effect of the TZDs on PGE2 is PPARγ-independent. Together, these findings indicate that it is possible to use a clinically available pharmacological intervention to suppress tumor-derived PGE2 by enhancing catabolism rather than blocking synthesis.

Footnotes

  • This work was supported by UCLA Specialized Programs of Research Excellence in Lung Cancer, National Institutes of Health grants P50-CA90388 and R01-CA111851, UC Tobacco-Related Disease Research Program (13RT-0031); Medical Research Funds from The Department of Veteran Affairs; and The Flight Attendant Medical Research Institute (FAMRI) Young Clinical Scientist Awards.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.033357.

  • ABBREVIATIONS: COX, cyclooxygenase; PG, prostaglandin; NSCLC, non–small-cell lung cancer; PGDH, 15-hydroxyprostaglandin dehydrogenase; TZD, thiazolidinedione; PPAR-γ, peroxisome proliferator-activated receptor-γ; DMSO, dimethyl sulfoxide; ELISA, enzyme-linked immunosorbent assay; GW9662, 2-chloro-5-nitrobenzanilide; dn, dominant negative; FBS, fetal bovine serum; siRNA, small interfering RNA; PGES, prostaglandin E synthase; mPGES1, microsomal prostaglandin E synthase; cPGES, cytosolic prostaglandin E synthase; PPRE, peroxisome proliferator-activated receptor response element.

    • Received December 12, 2006.
    • Accepted April 5, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (6)
Molecular Pharmacology
Vol. 71, Issue 6
1 Jun 2007
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Research ArticleArticle

Pioglitazone and Rosiglitazone Decrease Prostaglandin E2 in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Saswati Hazra, Raj K. Batra, Hsin H. Tai, Sherven Sharma, Xiaoyan Cui and Steven M. Dubinett
Molecular Pharmacology June 1, 2007, 71 (6) 1715-1720; DOI: https://doi.org/10.1124/mol.106.033357

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Research ArticleArticle

Pioglitazone and Rosiglitazone Decrease Prostaglandin E2 in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Saswati Hazra, Raj K. Batra, Hsin H. Tai, Sherven Sharma, Xiaoyan Cui and Steven M. Dubinett
Molecular Pharmacology June 1, 2007, 71 (6) 1715-1720; DOI: https://doi.org/10.1124/mol.106.033357
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