Langenfeld J, Lonardo F, Kiyokawa H, Passalaris T, Ahn M J, Rusch V, Dmitrovsky E
Laboratory of Molecular Medicine, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Oncogene. 1996 Nov 7;13(9):1983-90.
The retinoids are reported to reduce second primary aerodigestive tract tumors in patients with prior lung or head and neck carcinomas. Yet, the optimal retinoid useful for chemoprevention and those mechanisms linked to this chemoprevention are not identified. This study reports an in vitro model for carcinogen-induced transformation of immortalized human bronchial epithelial (BEAS-2B) cells that was adapted to study the anti-carcinogenic effects of all-trans-retinoic acid (RA). Following exposure to carcinogens: cigarette smoke condensate (CSC) or N-nitrosamine-4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK), BEAS-2B cells exhibited evidence of transformation. This included an increased anchorage independent growth or acquired ability to form tumors in athymic mice. This transformation was inhibited by RA as demonstrated by a lack of augmented anchorage independent growth or tumor formation in athymic mice for the cells treated with RA. The BEAS-2B cells transformed by NNK exhibited an increase in cyclin E expression which was associated with an increase in the cyclin E-Cdk2 kinase activity. Over-expression of human cyclin E by transfection shows cyclin E enhances the basal clonal growth of BEAS-2B cells. In both the parental and transformed BEAS-2B cells, RA down-regulated cyclin E protein levels which was associated with an inhibition of growth and an accumulation of cells in G1. The data reported here suggest the decline of cyclin E expression represents a potential mechanism for the RA-induced growth suppression which is linked to the anti-carcinogenic effects of RA. Thus, this study reports the adaption of an in vitro model of lung carcinogenesis suitable to test the activity of chemoprevention agents.
据报道，类视黄醇可减少先前患有肺癌或头颈癌的患者的第二原发性气消化道肿瘤。然而，尚未确定对化学预防有用的最佳类视黄醇以及与这种化学预防相关的机制。本研究报告了一种用于致癌物诱导的永生化人支气管上皮（BEAS-2B）细胞转化的体外模型，该模型适用于研究全反式维甲酸（RA）的抗癌作用。在暴露于致癌物香烟烟雾冷凝物（CSC）或N-亚硝胺-4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）后，BEAS-2B细胞表现出转化的迹象。这包括无锚定依赖性生长增加或在无胸腺小鼠中形成肿瘤的获得能力。如用RA处理的细胞在无胸腺小鼠中缺乏增强的无锚定依赖性生长或肿瘤形成所证明的，这种转化被RA抑制。由NNK转化的BEAS-2B细胞表现出细胞周期蛋白E表达增加，这与细胞周期蛋白E-Cdk2激酶活性增加相关。通过转染过表达人细胞周期蛋白E表明细胞周期蛋白E增强了BEAS-2B细胞的基础克隆生长。在亲本和转化后的BEAS-2B细胞中，RA下调细胞周期蛋白E蛋白水平，这与生长抑制和细胞在G1期的积累相关。此处报道的数据表明细胞周期蛋白E表达的下降代表了RA诱导的生长抑制的潜在机制，这与RA的抗癌作用相关。因此，本研究报告了一种适用于测试化学预防剂活性的肺癌发生体外模型的改编。
