title: Expression of aryl hydrocarbon receptor nuclear translocator enhances cisplatin resistance by upregulating MDR1 expression in cancer cells.
abstract: The identification of molecular pathways in cancer cells is important for understanding the cells' underlying biology and for designing effective cancer therapies. We demonstrate that the expression of aryl hydrocarbon receptor nuclear translocator (ARNT) is critical during the development of cisplatin resistance. The reduced expression of ARNT was correlated with cisplatin-induced cell death in drug-sensitive cells. In addition, suppression of ARNT reversed the characteristics of cisplatin-resistant cells, making these cells cisplatin-sensitive, and significantly enhanced caspase-3 activation, DNA fragmentation, and apoptosis. The inhibition of colony formation, regulated by cisplatin, was more significant in ARNT-knockdown cells than in parental cells. In a xenograft analysis of severe combined immunodeficiency mice, cisplatin also efficiently inhibited ARNT-deficient c4 tumors but not ARNT-containing vT2 tumor formation. Furthermore, the downregulation of multidrug resistance 1 (MDR1) expression and retention of drugs in cells caused by suppression of ARNT, resulting in the resensitization of drug-resistant cells to cisplatin, was observed. When overexpressed, ARNT interacted with Sp1 to enhance the expression of MDR1 through Sp1-binding sites on the MDR1 promoter, resulting in a reversal of the effect of cisplatin on cell death. In addition, ARNT-induced MDR1 expression was inhibited in Sp1-knockdown cells. These results reveal previously unrecognized, multifaceted functions of ARNT in establishing the drug-resistant properties of cancer cells by the upregulation of MDR1, highlighting ARNT's potential as a therapeutic target in an important subset of cancers.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan (Y.-Y.C., S.K., B.-K.C.); Department of Clinical Pharmacology and Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacology, Taipei Medical University, Taipei, Taiwan (W.-Chi.C.); Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (W.-Cha.C.); Department of Pharmacy, Taipei Medical University-Wanfang Hospital, Taipei, Taiwan (W.-Chi.C.); and Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan (B.-K.C.).
authors.forename: Ya-Yi
authors.initials: YY
authors.lastname: Chan
authors.forename: Sriram
authors.initials: S
authors.lastname: Kalpana
authors.forename: Wei-Chiao
authors.initials: WC
authors.lastname: Chang
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.forename: Ben-Kuen
authors.initials: BK
authors.lastname: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis* / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002945:Cisplatin