Ritzenthaler Jeffrey D, Roman Jesse, Han ShouWei
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Methods Mol Biol. 2009;512:309-23. doi: 10.1007/978-1-60327-530-9_17.
Lung carcinoma remains one of the most common malignant tumors in the world despite recent advancements in the development of new chemotherapeutic agents for its treatment. Therefore, novel approaches for drug target discovery play an important role in the effort to help extend its dismal 5-year survival rate (<15%). Many mechanisms contribute to oncogenic transformation in carcinoma cells in the lung and recent evidence indicates that the overproduction of prostaglandin E(2) (PGE(2)), and the prostag-landin E(2) receptor subtype, EP4, promote the growth and progression of human nonsmall cell lung carcinoma (NSCLC), the most common lung carcinoma. Peroxisome proliferator-activated receptor beta/ delta (PPARbeta/delta), one of the nuclear hormone ligand-dependent transcription factors, has recently been reported to be involved in tumorigeniCity. We have shown that NSCLC cells express PPARbeta/delta protein and that treatment with a selective PPARbeta/delta agonist, GW501516, stimulated the expression of EP4 and induced NSCLC cell proliferation. In addition, this PPARbeta/delta agonist also induced EP4 promoter activity through the binding of C/EBP to the NF-IL6 site in the EP4 promoter. Therefore, PPARbeta/delta activation represents a novel molecular mechanism for regulating human cancer cell growth.
尽管近年来用于治疗肺癌的新型化疗药物不断发展，但肺癌仍是世界上最常见的恶性肿瘤之一。因此，发现新的药物靶点的新方法对于提高肺癌患者令人沮丧的5年生存率（<15%）具有重要作用。肺癌细胞发生致癌转化涉及多种机制，最近的证据表明，前列腺素E2（PGE2）及其受体亚型EP4的过度表达促进了人类非小细胞肺癌（NSCLC，最常见的肺癌类型）的生长和进展。过氧化物酶体增殖物激活受体β/δ（PPARβ/δ）是一种核激素配体依赖性转录因子，最近有报道称其与肿瘤发生有关。我们发现NSCLC细胞表达PPARβ/δ蛋白，用选择性PPARβ/δ激动剂GW501516处理可刺激EP4的表达并诱导NSCLC细胞增殖。此外，这种PPARβ/δ激动剂还通过C/EBP与EP4启动子中NF-IL6位点的结合诱导EP4启动子活性。因此，激活PPARβ/δ代表了一种调节人类癌细胞生长的新分子机制。
