Expression of the retinoic acid-metabolizing enzyme CYP26A1 limits programmed cell death.
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 to trigger programmed cell death (apoptosis) in certain types of tumor cells. On the other hand, 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-related apoptosis-inducing ligand. This resistance could be reversed by pretreatment with ketoconazole, a broad-spectrum inhibitor of cytochrome P450 enzymes. In addition, synthetic retinoids Am80 (4[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid) and Am580 [4(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtamido)benzoic acid], 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.
Osanai
Makoto
M
Department of Biochemistry and Pathology, Division of Cell Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Petkovich
Martin
M
D017209:Apoptosis / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000378:metabolism*
D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase