This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Keith, R. L. Articles by Geraci, M. W. Search for Related Content PubMed PubMed Citation Articles by Keith, R. L. Articles by Geraci, M. W.

Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in Mice

¹ Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Denver VA Medical Center, Denver, Colorado; ² Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, ³ Department of Pathology, and ⁴ Departments of Medicine and Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado; ⁵ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and ⁶ Inhalation Toxicology Laboratory, Lovelace Respiratory Research Institute, Albuquerque, New Mexico

Increased pulmonary production of prostaglandin I₂ (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 lung-specific 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 I₂ levels in the transgenic animals, coupled with significantly decreased prostaglandin E₂ 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.

This article has been cited by other articles:

				T. R. Richens, D. J. Linderman, S. A. Horstmann, C. Lambert, Y.-Q. Xiao, R. L. Keith, D. M. Boe, K. Morimoto, R. P. Bowler, B. J. Day, et al. Cigarette Smoke Impairs Clearance of Apoptotic Cells through Oxidant-dependent Activation of RhoA Am. J. Respir. Crit. Care Med., June 1, 2009; 179(11): 1011 - 1021. [Abstract] [Full Text] [PDF]

				A. K. Bauer and E. A. Rondini Review Paper: The Role of Inflammation in Mouse Pulmonary Neoplasia Veterinary Pathology, May 1, 2009; 46(3): 369 - 390. [Abstract] [Full Text] [PDF]

				R. L. Keith Chemoprevention of Lung Cancer Proceedings of the ATS, April 15, 2009; 6(2): 187 - 193. [Abstract] [Full Text] [PDF]

				R. Nemenoff, A. M. Meyer, T. M. Hudish, A. B. Mozer, A. Snee, S. Narumiya, R. S. Stearman, R. A. Winn, M. Weiser-Evans, M. W. Geraci, et al. Prostacyclin Prevents Murine Lung Cancer Independent of the Membrane Receptor by Activation of Peroxisomal Proliferator-Activated Receptor {gamma} Cancer Prevention Research, October 1, 2008; 1(5): 349 - 356. [Abstract] [Full Text] [PDF]

				C.-C. Ho, Y.-C. Ling, L. W. Chang, H.-T. Tsai, M.-H. Tsai, and P. Lin 17-Beta Estradiol and Hydroxyestradiols Interact via the NF-Kappa B Pathway to Elevate Cyclooxygenase 2 Expression and Prostaglandin E2 Secretion in Human Bronchial Epithelial Cells Toxicol. Sci., August 1, 2008; 104(2): 294 - 302. [Abstract] [Full Text] [PDF]

				H. Orita, J. Coulter, E. Tully, F. P. Kuhajda, and E. Gabrielson Inhibiting Fatty Acid Synthase for Chemoprevention of Chemically Induced Lung Tumors Clin. Cancer Res., April 15, 2008; 14(8): 2458 - 2464. [Abstract] [Full Text] [PDF]

				S. Hazra, R. K. Batra, H. H. Tai, S. Sharma, X. Cui, and S. M. Dubinett Pioglitazone and Rosiglitazone Decrease Prostaglandin E2 in Non-Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase Mol. Pharmacol., June 1, 2007; 71(6): 1715 - 1720. [Abstract] [Full Text] [PDF]

				S. P. Nana-Sinkam, J. D. Lee, S. Sotto-Santiago, R. S. Stearman, R. L. Keith, Q. Choudhury, C. Cool, J. Parr, M. D. Moore, T. M. Bull, et al. Prostacyclin Prevents Pulmonary Endothelial Cell Apoptosis Induced by Cigarette Smoke Am. J. Respir. Crit. Care Med., April 1, 2007; 175(7): 676 - 685. [Abstract] [Full Text] [PDF]

				L. Yang, Y. Huang, R. Porta, K. Yanagisawa, A. Gonzalez, E. Segi, D. H. Johnson, S. Narumiya, and D. P. Carbone Host and Direct Antitumor Effects and Profound Reduction in Tumor Metastasis with Selective EP4 Receptor Antagonism Cancer Res., October 1, 2006; 66(19): 9665 - 9672. [Abstract] [Full Text] [PDF]

				G. J. Kelloff, S. M. Lippman, A. J. Dannenberg, C. C. Sigman, H. L. Pearce, B. J. Reid, E. Szabo, V. C. Jordan, M. R. Spitz, G. B. Mills, et al. Progress in Chemoprevention Drug Development: The Promise of Molecular Biomarkers for Prevention of Intraepithelial Neoplasia and Cancer--A Plan to Move Forward Clin. Cancer Res., June 15, 2006; 12(12): 3661 - 3697. [Abstract] [Full Text] [PDF]

				D. J. Kim, K.S. Prabhu, F. J. Gonzalez, and J. M. Peters Inhibition of chemically induced skin carcinogenesis by sulindac is independent of peroxisome proliferator-activated receptor-{beta}/{delta} (PPAR{beta}/{delta}) Carcinogenesis, May 1, 2006; 27(5): 1105 - 1112. [Abstract] [Full Text] [PDF]

				E. M. Poole, J. Bigler, J. Whitton, J. G. Sibert, J. D. Potter, and C. M. Ulrich Prostacyclin synthase and arachidonate 5-lipoxygenase polymorphisms and risk of colorectal polyps. Cancer Epidemiol. Biomarkers Prev., March 1, 2006; 15(3): 502 - 508. [Abstract] [Full Text] [PDF]

				E. Fosslien Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs Ann. Clin. Lab. Sci., October 1, 2005; 35(4): 347 - 385. [Abstract] [Full Text] [PDF]

				R. Nasrallah and R. L. Hebert Prostacyclin signaling in the kidney: implications for health and disease Am J Physiol Renal Physiol, August 1, 2005; 289(2): F235 - F246. [Abstract] [Full Text] [PDF]

				B. Rigas and K. Kashfi Cancer Prevention: A New Era beyond Cyclooxygenase-2 J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 1 - 8. [Abstract] [Full Text] [PDF]

				F. R. Hirsch and S. M. Lippman Advances in the Biology of Lung Cancer Chemoprevention J. Clin. Oncol., May 10, 2005; 23(14): 3186 - 3197. [Abstract] [Full Text] [PDF]