title: Activating transcription factor 4 confers a multidrug resistance phenotype to gastric cancer cells through transactivation of SIRT1 expression.
abstract: BACKGROUND
  Multidrug resistance (MDR) in gastric cancer remains a major challenge to clinical treatment. Activating transcription factor 4 (ATF4) is a stress response gene involved in homeostasis and cellular protection. However, the expression and function of ATF4 in gastric cancer MDR remains unknown. In this study, we investigate whether ATF4 play a role in gastric cancer MDR and its potential mechanisms.
  
  
  RESULTS
  We demonstrated that ATF4 overexpression confered the MDR phenotype to gastric cancer cells, while knockdown of ATF4 in the MDR variants induced re-sensitization. In this study we also showed that the NAD(+)-dependent histone deacetylase SIRT1 was required for ATF4-induced MDR effect in gastric cancer cells. We demonstrated that ATF4 facilitated MDR in gastric cancer cells through direct binding to the SIRT1 promoter, resulting in SIRT1 up-regulation. Significantly, inhibition of SIRT1 by small interfering RNA (siRNA) or a specific inhibitor (EX-527) reintroduced therapeutic sensitivity. Also, an increased Bcl-2/Bax ratio and MDR1 expression level were found in ATF4-overexpressing cells.
  
  
  CONCLUSIONS
  We showed that ATF4 had a key role in the regulation of MDR in gastric cancer cells in response to chemotherapy and these findings suggest that targeting ATF4 could relieve therapeutic resistance in gastric cancer.
authors.affiliation: Department of Gastroenterology and State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zhu
authors.forename: Limin
authors.initials: L
authors.lastname: Xia
authors.forename: Yongguo
authors.initials: Y
authors.lastname: Zhang
authors.forename: Honghong
authors.initials: H
authors.lastname: Wang
authors.forename: Wenjing
authors.initials: W
authors.lastname: Xu
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Xin
authors.forename: Yi
authors.initials: Y
authors.lastname: Gang
authors.forename: Sumei
authors.initials: S
authors.lastname: Sha
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D004249:DNA Damage; D015536:Down-Regulation / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D015533:Transcriptional Activation / Q000235:genetics*; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D051701:Activating Transcription Factor 4; C447939:SIRT1 protein, human; D056564:Sirtuin 1