Nemenoff Raphael, Meyer Amy M, Hudish Tyler M, Mozer Anthony B, Snee Amy, Narumiya Shuh, Stearman Robert S, Winn Robert A, Weiser-Evans Mary, Geraci Mark W, Keith Robert L
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA.
Cancer Prev Res (Phila). 2008 Oct;1(5):349-56. doi: 10.1158/1940-6207.CAPR-08-0145.
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, PGIS-overexpressing mice were crossed to mice that lack the IP receptor [IP(-/-)]. Carcinogen-induced 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 PPARgamma in the protection of prostacyclin against lung tumorigenesis. Iloprost, a stable prostacyclin analogue, activated PPARgamma 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 PPARgamma overexpression also developed fewer lung tumors. This reduction was not enhanced by administration of supplemental iloprost. These studies indicate that PPARgamma is a critical target for prostacyclin-mediated lung cancer chemoprevention and may also have therapeutic activity.
在化学物质和香烟烟雾诱导的小鼠肺癌模型中，前列环素合酶（PGIS）的过表达可降低肺肿瘤的多发性。前列环素通过单一的G蛋白偶联受体（IP）发出信号，该受体通过环磷酸腺苷发挥作用。为了确定该受体在前列环素对肺癌化学预防中的作用，将过表达PGIS的小鼠与缺乏IP受体的小鼠[IP(-/-)]进行杂交。致癌物诱导的肺肿瘤发生率在IP(+/+)、IP(+/-)和IP(-/-)小鼠中相似，PGIS的过表达在所有三组中均提供了同等的保护作用，这表明前列环素的保护作用不是通过IP的激活介导的。由于前列环素可激活核受体过氧化物酶体增殖物激活受体（PPAR）家族的成员，我们研究了PPARγ在前列环素预防肺肿瘤发生中的作用。伊洛前列素，一种稳定的前列环素类似物，可在未转化的支气管上皮细胞和一部分人非小细胞肺癌细胞系中激活PPARγ。给野生型小鼠喂食含伊洛前列素的食物会导致肺巨噬细胞增多，肺肿瘤形成减少。肺特异性过表达PPARγ的转基因动物也产生较少的肺肿瘤。补充伊洛前列素并未增强这种减少。这些研究表明，PPARγ是前列环素介导的肺癌化学预防的关键靶点，也可能具有治疗活性。
