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Received for publication August 4, 2004.
Revised January 29, 2005.
Accepted for publication February 8, 2005.
Vitamin A deficiency has been associated with increased incidence of certain types of cancer, however the mechanisms by which vitamin A depletion promotes tumorigenesis are poorly understood. In addition all-trans-retinoic acid (RA), the most active form of vitamin A metabolites, has been shown to limit carcinogenesis in animal models, and trigger programmed cell death (apoptosis) in certain types of tumor cells. Conversely, we show here that various cell lines overexpressing CYP26A1, a cytochrome P450 enzyme specifically involved in the catabolic inactivation of RA, exhibit increased resistance to various apoptogenic factors including death receptor ligands such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). This resistance could be reversed by pre-treatment with ketoconazole, a broad-spectrum inhibitor of cytochrome P450 enzymes. Also, synthetic retinoids Am80 and Am580 which are resistant to CYP26A1 metabolism can restore the sensitivity of these cells to apoptogens. Thus, these findings support the idea that CYP26 expression levels may play a role in determining cellular commitment to apoptosis, and increased RA metabolism may be at least partially responsible for these observed effects.
Key words:
Tumor necrosis factor, Cytochrome P450, Apoptosis, Mechanisms of cell killing/apoptosis
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