Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in Mice

Abstract

Increased pulmonary production of prostaglandin I 2 (prostacyclin) by lung-specific overexpression of prostacyclin synthase decreases lung tumor incidence and multiplicity in chemically induced murine lung cancer models. We hypothesized that pulmonary prostacyclin synthase overexpression would prevent lung carcinogenesis in tobacco-smoke exposed mice. Murine exposure to tobacco smoke is an established model of inducing pulmonary adenocarcinomas and allows for the testing of potential chemopreventive strategies. Transgenic FVB/N mice with lungspecific prostacyclin synthase overexpression were exposed to mainstream cigarette smoke for 22 weeks and then held unexposed for an additional 20 weeks. All of the exposed animals developed bronchiolitis analogous to the respiratory bronchiolitis seen in human smokers. The transgenic mice, when compared with smoke-exposed transgene negative littermates, had significant decreases in tumor incidence and multiplicity. Significantly fewer transgenics (6 of 15; 40%) developed tumors compared with the tumor incidence in wild-type littermates (16 of 19; 84%; Fisher's exact test, P ‫؍‬ 0.012). Tumor multiplicity was also significantly decreased in the transgenic animals (tg ؉ ‫؍‬ 0.4 ؎ 0.5 versus wild-type ‫؍‬ 1.2 ؎ 0.86 tumors/mouse; P < 0.001). Targeted prostaglandin levels at the time of sacrifice revealed significantly elevated prostaglandin I 2 levels in the transgenic animals, coupled with significantly decreased prostaglandin E 2 levels. Gene expression analysis of isolated type II pneumocytes suggests potential explanations for the observed chemoprevention, with Western blot analysis confirming decreased expression of cytochrome p450 2e1. These studies extend our previous studies and demonstrate that manipulation of prostaglandin production distal to cyclooxygenase significantly reduces lung carcinogenesis in a tobacco smoke exposure model, and gene expression studies show critical alterations in antioxidation, immune response, and cytokine pathways.

Peroxisome proliferator‐activated receptor δ as a molecular target to regulate lung cancer cell growth

“…These results suggest that PPARd-dependent growth control depends on a cytostatic effect based on G1 arrest but not a cytotoxic effect. It has been reported that the induction of COX-2 and subsequent overproduction of PGs except PGI 2 contribute to the appearance of malignant phenotypes in lung adenocarcinoma cells [6,14]. From these reports, it can be assumed that the overproduction of PGs by COX except PGI 2 attenuates the PPARd-dependent negative growth control of A549 cells, so we examined the effect of L-165041 treatment on the growth of A549 cells under COX inhibition by indomethacin.…”

“…From these reports, it is speculated that, in addition to the induction of COX-2, the suppression of PGI 2 production contributes to the development of lung adenocarcinoma. The downregulation of PGI 2 synthase is observed in lung adenocarcinoma tissue, and the expression of PGI 2 synthase in lungs leads to the reduced development of lung adenocarcinoma in mice [13,14]. However, it remains unclear which signaling pathway regulated by PGI 2 contributes to the reduction of lung cancer.…”

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

“…It has been known that PGD 2 and PGI 2 are anticarcinogenic agents (Keith et al, 2004;Park et al, 2007;Cathcart et al, 2010). PGD 2 is rapidly metabolized to 15-deoxy-D 12,14 -PGJ 2 , which inhibits tumor growth via a peroxisome proliferator-activated receptor g (PPARg)-dependent or -independent pathway (Scher and Pillinger, 2005;Mansure et al, 2009).…”

“…It is thus conceivable that the elevated PGD 2 may be functionally linked to the increased PPARg and the decreased NF-kB in tumor tissues of mPGES-1 KO mice. It was also shown that pulmonary PGI synthase overexpression suppressed tobacco smoke-induced lung carcinogenesis in mice (Keith et al, 2004), indicating that PGI 2 , as well as PGD 2 , can be regarded as an anti-carcinogenic PG. As shown in Figure 2, ablation of mPGES-1 resulted not only in the suppression of carcinogenic PGE 2 production, mPGES-1 promotes colon carcinogenesis Y Sasaki et al but also in the reciprocal upregulation of anti-carcinogenic PGD 2 /PGI 2 production.…”

Hypermethylation of the prostacyclin synthase (PTGIS) promoter is a frequent event in colorectal cancer and associated with aneuploidy

“…Different investigations have highlighted the importance of the PTGIS expression in preventing tumor growth and progression (Keith et al, 2002;Pradono et al, 2002;Cutler et al, 2003;Keith et al, 2004). It has been suggested that some of the protective effects of PTGIS overexpression may be attributable to apoptosis activation mediated by PPARd (Hatae et al, 2001).…”