Selective pulmonary prostacyclin synthase overexpression chemoprevents murine lung cancer and alters global gene expression

Keith, Robert L.; Miller, York E.; Gesell, Tracy L.; Moore, Matthew; Malkinson, Alvin M.; Geraci, Mark W.

doi:10.1016/s0169-5002(00)80752-7

Cited by 76 publications

(118 citation statements)

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“…PGI 2 is a relevant mediator that plays an important role in vascular biology, preventing thrombosis, acting as a potent vasorelaxant agent (1). It also has an inhibitory effect in carcinogenesis (53). Modulation of final specific PG synthases could be a useful approach for selective treatments.…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid induces PGI synthase expression in human endothelial cells

Camacho

Rodrı́guez

Salazar

et al. 2008

Journal of Lipid Research

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Retinoic acid (RA) exhibits anti-inflammatory, anti-tumor, and immuno-modulatory actions, and affects angiogenesis and thrombosis. Arachidonic acid (AA) metabolites are involved in all these processes. We explored the effect of RA on AA metabolism in human umbilical vein endothelial cells (HUVECs). 13-cis -RA increased the release of prostaglandin I 2 (PGI 2) , both spontaneous and thrombin-induced, in terms of 6-oxo-PGF 1a analyzed by enzyme-immunoassay. Coincubation with 13-cis-RA and interleukin-1b resulted in a synergic increase in the release of PGI 2 . Consistently, 13-cis -RA increased the ability of HUVECs to inhibit AA-induced platelet aggregation. 13-cis-RA did not induce cyclooxygenase-isoenzyme expression, determined by immunoblotting, or activity, evaluated by analyzing eicosanoids formed from exogenous labeled AA by HPLC. In contrast, RA induced PGI synthase (PGIS) activity and expression in terms of mRNA and protein determined by real-time PCR and Western blotting, respectively. Results from experiments with several species of RA and with retinoic acid receptor (RAR) and retinoid X receptor (RXR) antagonists showed that the effect of RA on PGIS expression was mediated by RAR. Actinomycin D and cycloheximide both inhibited RA-induced PGIS expression. Furthermore, RA increased PGIS transcriptional activity in transient transfection assays, an effect that was prevented by an RAR antagonist. These results reinforce the concept that RA could be beneficial for patients with cardiovascular risk.-Camacho, M., C. Rodríguez, J. Salazar, J. Martínez-González, J. Ribalta, J-R. Escudero, L. Masana, and L. Vila. Retinoic acid induces PGI synthase expression in human endothelial cells.

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Section: Discussionmentioning

confidence: 99%

Retinoic acid induces PGI synthase expression in human endothelial cells

Camacho

Rodrı́guez

Salazar

et al. 2008

Journal of Lipid Research

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“…Therefore, we hypothesized that transgenic mice overexpressing PGIS from a lung-specific promoter would prevent lung tumor formation. Using this murine model, we showed that PGIS expression significantly decreases lung tumor formation and burden in both chemical carcinogenesis as well as in tobaccosmoke exposure models (10,11).…”

Section: Introductionmentioning

confidence: 92%

Genetic and Epigenetic Regulation of the Human Prostacyclin Synthase Promoter in Lung Cancer Cell Lines

Stearman

Grady

Nana‐Sinkam

et al. 2007

Molecular Cancer Research

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The importance of the arachidonic acid pathway has been established in colon and lung cancers, as well as in inflammatory diseases. In these diseases, prostacyclin I 2 (PGI2) and prostaglandin E 2 (PGE2) are thought to have antagonistic activities, with PGI2 exerting anti-inflammatory and antiproliferative activities, whereas PGE2 is proinflammatory and antiapoptotic. In human lung cancer, prostacyclin synthase (PGIS) and PGI2 are down-regulated, whereas PGE2 synthase (PGES) and PGE2 are up-regulated. Murine carcinogenesis models of human lung cancer reciprocate the relationship between PGIS and PGES expression. PGIS-overexpressing transgenic mice are protected from carcinogen-and tobacco smoke -induced lung tumor formation, suggesting that PGI2 may play a role in chemoprevention. We investigated several potential mechanisms for the down-regulation of PGIS in human lung cancer. Using transcription reporter assays, we show that single nucleotide polymorphisms in the PGIS promoter can affect transcriptional activity. In addition, PGIS expression in several human lung cancer cell lines is silenced by CpG methylation, and we have mapped these sites across the variable number of tandem repeats (VNTR) sequence in the promoter, as well as CpGs within exon 1 and the first intron. Finally, using fluorescence in situ hybridization, we show that human lung cancer cell lines and lung cancer tissues do not have a loss of the PGIS genomic region but multiple copies. These results show that an individual's PGIS promoter haplotype can play an important role in the predisposition for lung cancer and CpG methylation provides an epigenetic mechanism for the down-regulated PGIS expression. (Mol Cancer Res 2007;5(3):295 -308)

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“…Transgenic Mice Overexpressing PPAR␥ Have Decreased COX-2 Expression and Are Protected against Developing Lung Tumors. To test the relationship between PPAR␥ and COX-2 expression in vivo, we developed transgenic mice with targeted overexpression of PPAR␥ in the type II alveolar epithelial cells of the lung, using the surfactant protein C promoter (Keith et al, 2002). Expression of PPAR␥ in type II cells isolated from Tgϩ animals was markedly increased compared with wild-type litter mates (Fig.…”

Section: Ppar␥ Inhibits Lung Tumorigenesis By Inhibition Of Cox-2 713mentioning

confidence: 99%

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

et al. 2007

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Pharmacological activators of peroxisome proliferator-activated receptor-␥ (PPAR␥) 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 PPAR␥ 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 E 2 (PGE 2 ). The goal of these studies was to identify the molecular mechanisms whereby PPAR␥ inhibits tumorigenesis. Increased PPAR␥ inhibited expression of COX-2 protein and promoter activity, resulting in decreased PGE 2 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-B activity. Pharmacological inhibition of PGE 2 production mimicked the effects of PPAR␥ on epithelial differentiation in three-dimensional culture, and exogenous PGE 2 reversed the effects of increased PPAR␥ activity. Transgenic mice overexpressing PPAR␥ 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 PGE 2 as a result of elevated COX-2 expression are critical for promoting lung tumorigenesis and that the antitumorigenic effects of PPAR␥ are mediated in part through blocking this pathway.

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Selective pulmonary prostacyclin synthase overexpression chemoprevents murine lung cancer and alters global gene expression

Cited by 76 publications

References 0 publications

Retinoic acid induces PGI synthase expression in human endothelial cells

Retinoic acid induces PGI synthase expression in human endothelial cells

Genetic and Epigenetic Regulation of the Human Prostacyclin Synthase Promoter in Lung Cancer Cell Lines

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

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