Ciglitazone mediates COX-2 dependent suppression of PGE2 in human non-small cell lung cancer cells

Hazra, Saswati; Dubinett, Steven M.

doi:10.1016/j.plefa.2007.05.006

Cited by 27 publications

(15 citation statements)

References 26 publications

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“…Notably, the inhibitory effects of rosiglitazone and ciglitazone, but not PGJ2, were reversed by a specific PPARγ antagonist GW9662, suggesting the involvement of PPARγ-dependent and -independent mechanisms [62] . Also, ciglitazone suppressed COX-2 mRNA expression and COX-2 promoter activity, while upregulating peroxisome proliferator response element promoter activity in NSCLC cells further suggesting a negative modulator role for PPARγ ligands on the COX-2/PGE2 pathway in NSCLC [63] . Of note, in vitro studies and xenograft models have demonstrated that elevated COX-2 expression is critical for promoting lung tumorigenesis, and that the anti-tumorigenic effects of PPARγ ligands are mediated through suppression of COX-2 via increased activity of PTEN, decreased levels of phospho-Akt, and inhibition of nuclear factor-kB (NF-kB) activity [64] .…”

Section: Pparγ Ligands and Cyclooxygenase-2-related Pathwaysmentioning

confidence: 89%

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Han

Roman²

2010

WJBC

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Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors and members of the nuclear receptor superfamily. Of the three PPARs identified to date (PPARγ, PPARβ/δ, and PPARα), PPARγ has been studied the most, in part because of the availability of PPARγ agonists (also known as PPARγ ligands) and its significant effects on the management of several human diseases including type 2 diabetes, metabolic syndrome, cardiovascular disease and cancers. PPARγ is expressed in many tumors including lung cancer, and its function has been linked to the process of lung cancer development, progression and metastasis. Studies performed in gynogenic and xenograft models of lung cancer showed decreased tumor growth and metastasis in animals treated with PPARγ ligands. Furthermore, data are emerging from retrospective clinical studies that suggest a protective role for PPARγ ligands on the incidence of lung cancer. This review summarizes the research being conducted in this area and focuses on the mechanisms and potential therapeutic effects of PPARγ ligands as a novel anti-lung cancer treatment strategy.

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Section: Pparγ Ligands and Cyclooxygenase-2-related Pathwaysmentioning

confidence: 89%

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Han

Roman²

2010

WJBC

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“…Cells were washed with PBS and whole-cell lysates were collected over ice using lysis buffer prepared according to standard methods (25). Protein concentrations were measured with a BCA proteinassay reagent (Pierce, Rockford, IL).…”

Section: Methodsmentioning

confidence: 99%

A Novel Molecular Pathway for Snail-Dependent, SPARC-Mediated Invasion in Non–Small Cell Lung Cancer Pathogenesis

Grant

Fishbein

Hong

et al. 2014

Cancer Prevention Research

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Definition of the molecular pathogenesis of lung cancer allows investigators an enhanced understanding of the natural history of the disease, thus fostering development of new prevention strategies. In addition to regulating epithelial-to-mesenchymal transition (EMT), the transcription factor Snail exerts global effects on gene expression. Our recent studies reveal that Snail is upregulated in non-small cell lung cancer (NSCLC), is associated with poor prognosis, and promotes tumor progression in vivo. Herein, we demonstrate that overexpression of Snail leads to upregulation of Secreted Protein, Acidic and Rich in Cysteine (SPARC) in models of premalignancy and established disease, as well as in lung carcinoma tissues in situ. Snail overexpression leads to increased SPARC-dependent invasion in vitro, indicating that SPARC may play a role in lung cancer progression. Bioinformatic analysis implicates TGF-β, ERK1/2, and miR-29b as potential intermediaries in Snail-mediated upregulation of SPARC. Both the TGF-β1 ligand and TGF-βR2 are upregulated following Snail overexpression. Treatment of human bronchial epithelial cell (HBEC) lines with TGF-β1 and inhibition of TGF-β1 mRNA expression modulated SPARC expression. Inhibition of MEK phosphorylation downregulated SPARC. MiR-29b is downregulated in Snail overexpressing cell lines, while overexpression of miR-29b inhibited SPARC expression. In addition, miR-29b was upregulated following ERK inhibition, suggesting a Snail-dependent pathway by which Snail activation of TGF-β and ERK signaling results in downregulation of miR-29b and subsequent upregulation of SPARC. Our discovery of pathways responsible for Snail-induced SPARC expression contributes to the definition of NSCLC pathogenesis.

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“…Although the Cox-2 gene contains a PPRE within its promoter [ 33 , 34 ], PPARγ-dependent and PPARγ-independent mechanisms both positively and negatively regulate Cox-2 gene transcription depending on cell- and stimulus-specific contexts [ 33 , 35 , 36 , 37 ]. Given Cox-2 expression was lower in DMBA + ROSI-treated PPARγ-WT tumours suggests MG cell-specific PPARγ activation may play a role in suppressing Cox-2 protein levels, which is similar to our findings with respect to mammary secretory epithelial-PPARγ [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Opposing roles for mammary epithelial-specific PPARγ signaling and activation during breast tumour progression

et al. 2015

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BackgroundAmong women worldwide, breast cancer is the most commonly diagnosed cancer, and the second leading cause of cancer-related deaths. Improved understanding of breast tumourigenesis may facilitate the development of more effective therapies. Peroxisome proliferator-activated receptor (PPAR)γ is a transcription factor that regulates genes involved in insulin sensitivity and adipogenesis. Previously, we showed, using 7,12-dimethylbenz [a] anthracene (DMBA)-treated haploinsufficient PPARγ mice, that PPARγ suppresses breast tumour progression; however, the PPARγ expressing cell types and mechanisms involved remain to be clarified. Here, the role of PPARγ expression and activation in mammary epithelial cells (MG) with respect to DMBA-mediated breast tumourigenesis was investigated.MethodsPPARγ MG knockout (PPARγ-MG KO) mice and their congenic, wild-type controls (PPARγ-WT) were treated once a week for six weeks by oral gavage with 1 mg DMBA dissolved in corn oil and maintained on a normal chow diet. At week 7, mice were randomly divided into those maintained on a normal chow diet (DMBA Only; PPARγ-WT: n = 25 and PPARγ-MG KO: n = 39) or those receiving a diet supplemented with the PPARγ ligand, rosiglitazone (ROSI, 4 mg/kg/day) (DMBA + ROSI; PPARγ-WT: n = 34 and PPARγ-MG KO: n = 17) for the duration of the 25-week study.ResultsCompared to DMBA Only-treated PPARγ-WTs, both breast tumour susceptibility and serum levels of proinflammatory and chemotactic cytokines, namely IL-4, eotaxin, GM-CSF, IFN-γ, and MIP-1α, were decreased among PPARγ-MG KOs. Cotreatment with ROSI significantly reduced breast tumour progression among PPARγ-WTs, correlating with increased BRCA1 and decreased VEGF and COX-2 protein expression levels in breast tumours; whereas, surprisingly DMBA + ROSI-treated PPARγ-MG KOs showed increased breast tumourigenesis, correlating with activation of COX-2.ConclusionThese novel data suggest MG-specific PPARγ expression and signaling is critical during breast tumourigenesis, and may serve as a strong candidate predictive biomarker for response of breast cancer patients to the use of therapeutic strategies that include PPARγ ligands.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0347-8) contains supplementary material, which is available to authorized users.

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Ciglitazone mediates COX-2 dependent suppression of PGE2 in human non-small cell lung cancer cells

Cited by 27 publications

References 26 publications

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

A Novel Molecular Pathway for Snail-Dependent, SPARC-Mediated Invasion in Non–Small Cell Lung Cancer Pathogenesis

Opposing roles for mammary epithelial-specific PPARγ signaling and activation during breast tumour progression

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