Overexpression of prostacyclin synthase (PGIS) decreases lung tumor multiplicity in chemical-and cigarette-smoke-induced murine lung cancer models. Prostacyclin signals through a single G-protein-coupled receptor (IP), which signals through cyclic AMP. To determine the role of this receptor in lung cancer chemoprevention by prostacyclin, PGISoverexpressing mice were crossed to mice that lack the IP receptor [IP(−/−)]. Carcinogeninduced lung tumor incidence was similar in IP(+/+), IP(+/−), and IP(−/−) mice, and overexpression of PGIS gave equal protection in all three groups, indicating that the protective effects of prostacyclin are not mediated through activation of IP. Because prostacyclin can activate members of the peroxisomal proliferator-activated receptor (PPAR) family of nuclear receptors, we examined the role of PPARγ in the protection of prostacyclin against lung tumorigenesis. Iloprost, a stable prostacyclin analogue, activated PPARγ in nontransformed bronchial epithelial cells and in a subset of human non-small-cell lung cancer cell lines. Iloprost-impregnated chow fed to wild-type mice resulted in elevated lung macrophages and decreased lung tumor formation. Transgenic animals with lung-specific PPARγ overexpression also developed fewer lung tumors. This reduction was not enhanced by administration of supplemental iloprost. These studies indicate that PPARγ is a critical target for prostacyclin-mediated lung cancer chemoprevention and may also have therapeutic activity.In the United States, lung cancer continues to be the leading cause of cancer death in both men and women, and worldwide the lung cancer epidemic will result in millions of cases yearly (1). Whereas tobacco abstinence and smoking cessation are the critical first steps in reducing lung cancer rates, the majority of U.S. lung cancers are diagnosed in former smokers. To date, no effective chemopreventive agents have been discovered. The large at-risk population (current and former smokers) and poor 5-year lung cancer survival rates (2) underscore the need for a better understanding of chemopreventive mechanisms and effective agents.Prostaglandins play an important role in lung tumorigenesis, and prostaglandin manipulation has been investigated for lung cancer chemoprevention. Cyclooxygenase (COX) inhibition decreases levels of prostaglandins, and large epidemiologic surveys have shown fewer lung cancers in "frequent aspirin users" (3). Human trials evaluating COX inhibition and lung cancer chemoprevention are currently being conducted, but conflicting data in murine studies evaluating the role of nonspecific COX or selective COX-2 inhibition make interpretation of these results difficult. Studies using nonselective COX inhibitors have shown inhibition of lung tumorigenesis in mice (4, 5). However, mice receiving celecoxib (a selective COX-2 inhibitor) showed reduced pulmonary inflammation, but no differences in tumor multiplicity, and an actual increase in tumor size after exposure to an initiator-promoter model of lung tumorigen...
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.
Epidemiological investigations suggest that chronic lung inflammation increases lung cancer risk. Pharmacologic and genetic evidence in mouse models indicates that lipid mediators released during pulmonary inflammation enhance lung tumor formation. Cytosolic phospholipase A2 (cPLA2) catalyzes arachidonic acid (AA) release from membrane phospholipids. AA can then lead to the synthesis of several classes of lipid mediators, including prostaglandin (PG) biosynthesis through the cyclooxygenase (COX) pathway. We investigated a role for cPLA2 in mouse lung tumorigenesis by using mice genetically deficient in cPLA2. After multiple urethane injections into cPLA2 null mice and wild-type littermates, the number of lung tumors was determined. cPLA2 null mice developed 43% fewer tumors (from 16 +/- 2 to 9 +/- 2 tumors/mouse; P < 0.05) than wild-type littermates. cPLA2, COX-1, COX-2 and microsomal prostaglandin E2 synthase (mPGES), examined by immunohistochemistry, are present in alveolar and bronchiolar epithelia and in alveolar macrophages in lungs from naive mice and tumor-bearing mice. Tumors express higher levels of each of these four enzymes than control lungs, as determined by immunoblotting. No differences were detected in the contents of COX-1, COX-2 and mPGES between wild-type and cPLA2 null mice. Although the steady-state levels of prostaglandin E2 and prostaglandin I2 in lung tissue extracts prepared from wild-type or cPLA2 (-/-) mice were not significantly different, both prostaglandins markedly increased in tumors from wild-type mice, an increase that was significantly blunted in tumors from cPLA2 (-/-) mice. These results demonstrate a role for cPLA2 in mouse lung tumorigenesis that may be mediated by decreased prostaglandin synthesis.
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