© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 4, 373-379,
February 17, 1999
© 1999 Oxford University Press
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Cyclin D1 Proteolysis: a Retinoid Chemoprevention Signal in Normal, Immortalized, and Transformed Human Bronchial Epithelial Cells
Affiliations of authors: J. O. Boyle (Laboratory of Molecular Medicine and Head and Neck Service), J. Langenfeld (Laboratory of Molecular Medicine and Thoracic Surgery Service), F. Lonardo (Laboratory of Molecular Medicine and Department of Pathology), D. Sekula (Laboratory of Molecular Medicine), V. Rusch (Laboratory of Molecular Medicine and Thoracic Surgery Service), E. Dmitrovsky (Laboratory of Molecular Medicine and Molecular Pharmacology and Therapeutics Program), Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY; P. Reczek, Bristol-Myers Squibb Pharmaceutical Research Institute, Buffalo, NY; M. I. Dawson, Retinoid Program, SRI International, Menlo Park, CA.
Correspondence to: Jay O. Boyle, M.D., Head and Neck Service,Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (e-mail: jboyle{at}mskcc.org).
Present address:D. Sekula, Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH.
Present address: E. Dmitrovsky, Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH.
BACKGROUND: Retinoids (derivatives of vitamin A) are reported to reduce the occurrence of some second primary cancers, including aerodigestive tract tumors. In contrast, ß-carotene does not reduce the occurrence of primary aerodigestive tract cancers. Mechanisms explaining these effective retinoid and ineffective carotenoid chemoprevention results are poorly defined. Recently, the all-trans-retinoic acid (RA)-induced proteolysis of cyclin D1 that leads to the arrest of cells in G1 phase of the cell cycle was described in human bronchial epithelial cells and is a promising candidate for such a mechanism. In this study, we have investigated this proteolysis as a common signal used by carotenoids or receptor-selective and receptor-nonselective retinoids. METHODS: We treated cultured normal human bronchial epithelial cells, immortalized human bronchial epithelial cells (BEAS-2B), and transformed human bronchial epithelial cells (BEAS-2BNNK) with receptor-selective or receptor-nonselective retinoids or with carotenoids and studied the effects on cell proliferation by means of tritiated thymidine incorporation and on cyclin D1 expression by means of immunoblot analysis. We also examined whether calpain inhibitor I, an inhibitor of the 26S proteasome degradation pathway, affected the decline (i.e., proteolysis) of cyclin D1. RESULTS: Receptor-nonselective retinoids were superior to the carotenoids studied in mediating the decline in cyclin D1 expression and in suppressing the growth of bronchial epithelial cells. Retinoids that activated retinoic acid receptor ß or retinoid X receptor pathways preferentially led to a decrease in the amount of cyclin D1 protein and a corresponding decline in growth. The retinoid-mediated degradation of cyclin D1 was blocked by cotreatment with calpain inhibitor I. CONCLUSIONS: Retinoid-dependent cyclin D1 proteolysis is a common chemoprevention signal in normal and neoplastic human bronchial epithelial cells. In contrast, carotenoids did not affect cyclin D1 expression. Thus, the degradation of cyclin D1 is a candidate intermediate marker for effective retinoid-mediated cancer chemoprevention in the aerodigestive tract.
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