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.