Retinoic acid 4-hydroxylase-mediated catabolism of all-trans retinoic acid and the cell proliferation in head and neck squamous cell carcinoma.
All-trans retinoic acid (RA) can be catabolized to polar metabolites by microsomal P450s (P450). The aim of this study was to confirm if retinoic acid 4-hydroxylase (CYP26) is a P450 induced by RA and to investigate the role of cellular RA binding proteins (CRABPs), using a slow catabolizer, AMC-HN-4, and a rapid catabolizer, AMC-HN-6. Also, we analyzed the effect of RA catabolism on cell proliferation of head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. Both cell lines weakly expressed CYP26 and CRABPs, but RA induced CYP26 only in AMC-HN-6. The sensitivity to RA was variable by the amount of CYP26, and the rapid catabolism by CYP26 made AMC-HN-6 resistant to RA in vitro. In addition, The RA had a stronger effect on the inhibition of tumor growth of AMC-HN-4 than that of AMC-HN-6 in vivo. Conclusively, the CYP26 activity might be one essential factor for the RA sensitivity, but in cells showing induction of CYP26, the RA sensitivity is inversely related to the rate of RA catabolism.
Kim
Sang Yoon
SY
Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Yoo
Seung Joo
SJ
Kwon
Hyun Ja
HJ
Kim
Sun Hee
SH
Byun
Youngro
Y
Lee
Kwang-Sun
KS
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003470:Culture Media; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003470:Culture Media; D018168:Receptors, Retinoic Acid; C082927:retinoic acid binding protein I, cellular; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase