Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1.
Vitamin A deficiency (VAD) is associated with increased susceptibility to carcinogenesis in animal models and elevated risk for a number of human cancers. Here, we found that CYP26A1, the gene encoding a cytochrome P450 enzyme specifically involved in metabolic inactivation of retinoic acid (RA), the most active vitamin A derivative, is highly expressed in 42% (27/65) of primary breast cancers. We also showed that enhanced expression of CYP26A1 suppresses cellular responses to anoikis and consequently promotes anchorage-independent growth. This transformed phenotype was sufficient to markedly increase tumorigenic and metastatic potential. Suppression of CYP26A1 significantly reversed the CYP26A1-mediated oncogenic characteristics, suggesting a direct link between intracellular RA status and tumorigenicity. Our observations provide strong evidence for oncogenic and cell survival properties of CYP26A1 in carcinogenesis, and suggest mechanisms whereby VAD might promote cancer development.
Osanai
M
M
Department of Pathology, Kochi University School of Medicine, Nankoku, Kochi, Japan. osanaim@kochi-u.ac.jp
Sawada
N
N
Lee
G-H
GH
D000818:Animals; D023102:Anoikis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000502:physiology; D004195:Disease Models, Animal; D004347:Drug Interactions; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000209:etiology; D000072516:Retinoic Acid 4-Hydroxylase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014801:Vitamin A / Q000494:pharmacology*; D014802:Vitamin A Deficiency / Q000150:complications*
D002273:Carcinogens; D014801:Vitamin A; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607080:Cyp26a1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase