Antitumorigenic effects of peroxisome proliferator-activated receptor-γ in non-small-cell lung cancer cells are mediated by suppression of cyclooxygenase-2 via inhibition of nuclear factor-κB

Yvette Bren-Mattison, Amy M. Meyer, Vicki Van Putten, Howard Li, Katherine Kuhn, Robert Stearman, Mary Weiser-Evans, Robert A. Winn, Lynn E. Heasley, Raphael A. Nemenoff

Research output: Contribution to journalArticle

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Abstract

Pharmacological activators of peroxisome proliferator-activated receptor-γ (PPARγ) inhibit growth of non-small-cell lung cancer (NSCLC) cell lines in vitro and in xenograft models. Because these agents engage off-target pathways, we have assessed the effects of PPAR by overexpressing the protein in NSCLC cells. We reported previously that increased PPARγ inhibits transformed growth and invasiveness and promotes epithelial differentiation in a panel of NSCLC expressing oncogenic K-Ras. These cells express high levels of cyclooxygenase-2 (COX-2) and produce high levels of prostaglandin E2 (PGE2). The goal of these studies was to identify the molecular mechanisms whereby PPARγ inhibits tumorigenesis. Increased PPARγ inhibited expression of COX-2 protein and promoter activity, resulting in decreased PGE2 production. Suppression of COX-2 was mediated through increased activity of the tumor suppressor phosphatase and tensin homolog, leading to decreased levels of phospho-Akt and inhibition of nuclear factor-κB activity. Pharmacological inhibition of PGE2 production mimicked the effects of PPARγ on epithelial differentiation in three-dimensional culture, and exogenous PGE2 reversed the effects of increased PPARγ activity. Transgenic mice overexpressing PPARγ under the control of the surfactant protein C promoter had reduced expression of COX-2 in type II cells and were protected against developing lung tumors in a chemical carcinogenesis model. These data indicate that high levels of PGE2 as a result of elevated COX-2 expression are critical for promoting lung tumorigenesis and that the antitumorigenic effects of PPARγ are mediated in part through blocking this pathway.

Original languageEnglish (US)
Pages (from-to)709-717
Number of pages9
JournalMolecular Pharmacology
Volume73
Issue number3
DOIs
StatePublished - Mar 2008
Externally publishedYes

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Peroxisome Proliferator-Activated Receptors
Complement Factor B
Cyclooxygenase 2
Non-Small Cell Lung Carcinoma
Dinoprostone
Carcinogenesis
Pharmacology
Chemical Models
Lung
Growth
Protein C
Phosphoric Monoester Hydrolases
Heterografts
Surface-Active Agents
Transgenic Mice
Neoplasms
Proteins
Cell Line

ASJC Scopus subject areas

  • Pharmacology

Cite this

Antitumorigenic effects of peroxisome proliferator-activated receptor-γ in non-small-cell lung cancer cells are mediated by suppression of cyclooxygenase-2 via inhibition of nuclear factor-κB. / Bren-Mattison, Yvette; Meyer, Amy M.; Van Putten, Vicki; Li, Howard; Kuhn, Katherine; Stearman, Robert; Weiser-Evans, Mary; Winn, Robert A.; Heasley, Lynn E.; Nemenoff, Raphael A.

In: Molecular Pharmacology, Vol. 73, No. 3, 03.2008, p. 709-717.

Research output: Contribution to journalArticle

Bren-Mattison, Yvette ; Meyer, Amy M. ; Van Putten, Vicki ; Li, Howard ; Kuhn, Katherine ; Stearman, Robert ; Weiser-Evans, Mary ; Winn, Robert A. ; Heasley, Lynn E. ; Nemenoff, Raphael A. / Antitumorigenic effects of peroxisome proliferator-activated receptor-γ in non-small-cell lung cancer cells are mediated by suppression of cyclooxygenase-2 via inhibition of nuclear factor-κB. In: Molecular Pharmacology. 2008 ; Vol. 73, No. 3. pp. 709-717.
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