INHIBITED TRANSFORMATION OF IMMORTALIZED HUMAN BRONCHIAL EPITHELIAL-CELLS BY RETINOIC ACID IS LINKED TO CYCLIN-E DOWN-REGULATION

The retinoids are reported to reduce second primary aerodigestive trac t 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 immortalize d human bronchial epithelial (BEAS-2B) cells that was adapted to study the anticarcinogenic effects of all-trans-retinoic acid (RA). Followi ng exposure to carcinogens: cigarette smoke condensate (CSC) or N-nitr osamine-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 at hymic mice. This transformation was inhibited by RA as demonstrated by a lack of augmented anchorage independent growth or tumor formation i n athymic mice for the cells treated with RA. The BEAS-2B cells transf ormed by NNK exhibited an increase in cyclin E expression which was as sociated with an increase in the cyclin E-Cdk2 kinase activity. Over-e xpression of human cyclin E by transfection shows cyclin E enhances th e basal clonal growth of BEAS-2B cells. In both the parental and trans formed BEAS-2B cells, RA down-regulated cyclin E protein levels which was associated with an inhibition of growth and an accumulation of cel ls in G1. The data reported here suggest the decline of cyclin E expre ssion represents a potential mechanism for the RA-induced growth suppr ession which is linked to the anti-carcinogenic effects of RA. Thus, t his study reports the adaption of an in vitro model of lung carcinogen esis suitable to test the activity of chemoprevention agents.