title: Stimulus-induced expression of the ABCG2 multidrug transporter in HepG2 hepatocarcinoma model cells involves the ERK1/2 cascade and alternative promoters.
abstract: The ATP-binding cassette G subfamily member ABCG2 protein is involved in drug resistance of various types of cancer including hepatocellular carcinoma (HCC). The transcriptional regulation of the ABCG2 gene was shown to depend on various transcription factors, and three alternative promoters were described. Here we aimed to decipher the role of hepatocyte growth factor (HGF) and the related kinase cascades on the expression of ABCG2 and the role of the different promoters in this process in the HepG2 human HCC cell line. We observed that HGF treatment increased the amount of ABCG2 on the cell surface in parallel with an increased ABCG2 transcription. ABCG2 mRNA expression was also increased by EGF, oxidative stress or activation of the aryl hydrocarbon receptor, while decreased by TGFb. Treatment with U0126, a specific inhibitor of the ERK1/2 cascade, prevented the HGF and the oxidative stress induced ABCG2 upregulation. We also show that the regulation of ABCG2 by various modulators involve specific alternative promoters. In conclusion, we demonstrate a unique role of the ERK1/2 cascade on ABCG2 modulation in HepG2, and the differential use of the alternative ABCG2 promoters in this cell line. This study reveals the molecular participants of ABCG2 overexpression as new potential treatment targets in HCC.
authors.affiliation: Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Karolina ut 29, 1113 Budapest, Hungary. hdeboussac@enzim.hu
authors.forename: Hugues
authors.initials: H
authors.lastname: de Boussac
authors.forename: Tamás I
authors.initials: TI
authors.lastname: Orbán
authors.forename: György
authors.initials: G
authors.lastname: Várady
authors.forename: Borbála
authors.initials: B
authors.lastname: Tihanyi
authors.forename: Caroline
authors.initials: C
authors.lastname: Bacquet
authors.forename: Anna
authors.initials: A
authors.lastname: Brózik
authors.forename: András
authors.initials: A
authors.lastname: Váradi
authors.forename: Balázs
authors.initials: B
authors.lastname: Sarkadi
authors.forename: Tamás
authors.initials: T
authors.lastname: Arányi
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress; D010703:Phorbol Esters / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists; D014158:Transcription, Genetic
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D010703:Phorbol Esters; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases