期刊
EUROPEAN JOURNAL OF CANCER
卷 45, 期 16, 页码 2882-2892出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2009.07.010
关键词
Hypoxia; HIF-1 alpha; Cytochrome P450; CYP3A4; Hepatocellular carcinoma; HepaRG; Chemoresistance
类别
资金
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Centre National de la Recherche Scientificlue (CNRS)
- Conseil Regional de Bretagne
- Association pour la Recherche contre le Cancer (ARC)
- INSERM/Japan Society for the Promotion of Science (JSPS)
- GIS therapie cellulaire de Rennes
- National Institute of Biomedical Innovation and Astellas Pharma Inc.
- Ligue Nationale contre le Cancer
Weak blood irrigation within solid tumours including hepatocellular carcinomas (HCCs) plays an important role in resistance to anticancer drugs by decreasing accessibility of cytotoxic agents to tumour cells. Reduced oxygen levels, or hypoxia, also contribute to drug resistance because many anticancer drugs require molecular oxygen to be cytotoxic. Our aim was to develop a new in vitro model mimicking hypoxic cells within HCCs in order to further explore the molecular responses to hypoxia, including regulation of drug-metabolising enzymes (DMEs) expression. For this purpose, we used the highly differentiated human hepatoma HepaRG cells cultured under either normoxic or hypoxic (24 h at 1% 02) conditions. Gene and protein expressions were investigated by quantitative PCR and immunoblotting, respectively. We showed that HepaRG cells adapt to prolonged moderate hypoxia by a switch from aerobic to anaerobic glycolysis and a repression of critical genes involved in amino acid, lipid and ethanol metabolisms. importantly, expression of several DMEs (particularly cytochromes P450 (CYPs) and phase II enzymes) and xenosensors (CAR, PXR and AhR) was down-regulated and CYPs activities (using testosterone and paclitaxel as substrates) were decreased during hypoxia. in addition, a new role for HIF-1 alpha in the repression of CYP3A4 is demonstrated in cells treated with chemical inducers of HIF-1 alpha, cobalt chloride or desferrioxamine, and by transfecting untreated HepaRG cells with HIF-1 alpha expression vector, In conclusion, HepaRG cells cultured under hypoxia might mimic metabolic changes occurring within poorly irrigated differentiated HCCs. Furthermore, hypoxia down-regulates hepatic DMEs, a phenomenon that might compromise chemotherapy effectiveness in HCC treatment. Thus, HepaRG cells might represent a new in vitro model to test anticancer agents in hypoxic versus normoxic conditions. (C) 2009 Elsevier Ltd. All rights reserved.
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