| Abstract
| - BACKGROUND: Retinoids (derivatives of vitamin A) arereported to reduce the occurrence of some second primary cancers,including aerodigestive tract tumors. In contrast, β-carotene doesnot reduce the occurrence of primary aerodigestive tract cancers.Mechanisms explaining these effective retinoid and ineffectivecarotenoid chemoprevention results are poorly defined. Recently, theall-trans-retinoic acid (RA)-induced proteolysis of cyclin D1that leads to the arrest of cells in G1 phase of the cellcycle was described in human bronchial epithelial cells and is apromising candidate for such a mechanism. In this study, we haveinvestigated this proteolysis as a common signal used by carotenoids orreceptor-selective and receptor-nonselective retinoids.METHODS: We treated cultured normal human bronchial epithelialcells, immortalized human bronchial epithelial cells (BEAS-2B), andtransformed human bronchial epithelial cells (BEAS-2BNNK)with receptor-selective or receptor-nonselective retinoids or withcarotenoids and studied the effects on cell proliferation by means oftritiated thymidine incorporation and on cyclin D1 expression by meansof immunoblot analysis. We also examined whether calpain inhibitor I,an inhibitor of the 26S proteasome degradation pathway, affected thedecline (i.e., proteolysis) of cyclin D1. RESULTS:Receptor-nonselective retinoids were superior to the carotenoidsstudied in mediating the decline in cyclin D1 expression and insuppressing the growth of bronchial epithelial cells. Retinoids thatactivated retinoic acid receptor β or retinoid X receptor pathwayspreferentially led to a decrease in the amount of cyclin D1 protein anda corresponding decline in growth. The retinoid-mediated degradation ofcyclin D1 was blocked by cotreatment with calpain inhibitor I.CONCLUSIONS: Retinoid-dependent cyclin D1 proteolysis is acommon chemoprevention signal in normal and neoplastic human bronchialepithelial cells. In contrast, carotenoids did not affect cyclin D1expression. Thus, the degradation of cyclin D1 is a candidateintermediate marker for effective retinoid-mediated cancer chemoprevention inthe aerodigestive tract.
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