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 PPARγ 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.
Footnotes
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This work was supported by grants CA103618, CA108610, and CA58187 from the National Institutes of Health.
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Y.B.-M. and A.M.M. contributed equally to this work.
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ABBREVIATIONS: PPARγ, peroxisome proliferator-activated receptor-γ; NSCLC, nonsmall cell lung cancer; TZD, thiazolinedione; COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; NF-κB, nuclear factor κB; PTEN, phosphatase and tensin homolog; AA, arachidonic acid; mPGES, microsomal prostaglandin E2 synthase; IKK, IκB kinase complex; DMSO, dimethyl sulfoxide; 3-D, three dimensional; PBS, phosphate-buffered saline; RIPA, radioimmunoprecipitation assay; ELISA, enzyme-linked immunosorbent assay; bp, base pair; IL, interleukin; DN, dominant-negative; Luc, luciferase; PGDH, 15-hydroxyprostaglandin dehydrogenase; β-gal, β-galactosidase; LNCX, empty vector; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PI-3, phosphatidylinositol-3; T007, T0070907, 2-chloro-5-nitro-N-4-pyridinyl-benzamide; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride.
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↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
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↵1 Current affiliation: Sporian Microsystems Inc., Lafayette, Colorado.
- Received September 19, 2007.
- Accepted November 30, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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