title: Overexpression of CYP3A4, but not of CYP2D6, promotes hypoxic response and cell growth of Hep3B cells.
abstract: Cytochrome P450s (P450s) contribute to carcinogenesis by activating procarcinogens and also metabolize anti-cancer drugs. The activity and protein levels of P450s are important in cancer risk and in cancer therapy. In this study, we found that overexpression of CYP3A4 induced growth of a human hepatoma cell line, Hep3B. Overexpression of CYP2D6, by comparison, decreased cell growth. An inhibitor of CYP3A4, ketoconazole, significantly suppressed the growth of Hep3B cells overexpressing CYP3A4, but an inhibitor of CYP2D6, quinidine, did not restore Hep3B cell growth to baseline levels. Overexpression of CYP3A4 increased the production of reactive oxygen species, but this was not the cause of the CYP3A4-induced growth. Previously, we showed that CYP3A4 can produce epoxyeicosatrienoic acids (EETs) from arachidonic acid. The CYP3A4-enhanced cell growth was attenuated by a putative EET receptor antagonist, 14,15-EEZE. CYP3A4 promoted progression of the cell cycle from the G1 to the S phase. CYP3A4 also induced a hypoxic response of Hep3B cells, detected as enhanced erythropoietin gene expression (a typical hypoxic response). The cell growth promoted by CYP3A4 was inhibited by PI3K inhibitor LY294002. These results suggest that CYP3A4 plays an important role in tumor progression, independent of the activation of carcinogens and metabolism of anti-cancer drugs.
authors.affiliation: Research Center for Environmental Bioscience and Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, Sanda, Japan.
authors.forename: Ami
authors.initials: A
authors.lastname: Oguro
authors.forename: Koichi
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Funae
authors.forename: Susumu
authors.initials: S
authors.lastname: Imaoka
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000494:pharmacology; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D002453:Cell Cycle; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D015777:Eicosanoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011802:Quinidine / Q000494:pharmacology; D012313:RNA / Q000032:analysis; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection
chemical_list: C494022:14,15-eicosa-5-enoic acid; D058888:14-alpha Demethylase Inhibitors; D002867:Chromones; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007546:Isoquinolines; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D016718:Arachidonic Acid; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012313:RNA; D008156:Luciferases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D015126:8,11,14-Eicosatrienoic Acid; D011802:Quinidine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D007654:Ketoconazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one