title: An increase in reactive oxygen species by deregulation of ARNT enhances chemotherapeutic drug-induced cancer cell death.
abstract: BACKGROUND
  Unique characteristics of tumor microenvironments can be used as targets of cancer therapy. The aryl hydrocarbon receptor nuclear translocator (ARNT) is an important mediator of tumor progression. However, the functional role of ARNT in chemotherapeutic drug-treated cancer remains unclear.
  
  
  RESULTS
  Here, we found that knockdown of ARNT in cancer cells reduced the proliferation rate and the transformation ability of those cells. Moreover, cisplatin-induced cell apoptosis was enhanced in ARNT-deficient cells. Expression of ARNT also decreased in the presence of cisplatin through proteasomal degradation pathway. However, ARNT level was maintained in cisplatin-treated drug-resistant cells, which prevented cell from apoptosis. Interestingly, reactive oxygen species (ROS) dramatically increased when ARNT was knocked down in cancer cells, enhancing cisplatin-induced apoptosis. ROS promoted cell death was inhibited in cells treated with the ROS scavenger, N-acetyl-cysteine (NAC).
  
  
  CONCLUSIONS
  These results suggested that the anticancer activity of cisplatin is attributable to its induction of the production of ROS by ARNT degradation. Targeting ARNT could be a potential strategy to eliminate drug resistance in cancer cells.
authors.affiliation: Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan, ROC; The Center of General Education, Chia Nan University of Pharmacy and Science, Tainan, Taiwan, ROC.
authors.forename: Jiunn-Min
authors.initials: JM
authors.lastname: Shieh
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Chih-Jie
authors.initials: CJ
authors.lastname: Shen
authors.affiliation: Department of Clinical Pharmacology, and Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacology, Taipei Medical University, Taipei, Taiwan; Department of Pharmacy, Taipei Medical University-Wanfang Hospital, Taipei, Taiwan, ROC.
authors.forename: Wei-Chiao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Institute of Biochemistry, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Ya-Yi
authors.initials: YY
authors.lastname: Chan
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Wan-Chen
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan, ROC; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Ben-Kuen
authors.initials: BK
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D053148:Caspase 3; D002945:Cisplatin