title: Activating transcription factor 4 mediates a multidrug resistance phenotype of esophageal squamous cell carcinoma cells through transactivation of STAT3 expression.
abstract: Multidrug resistance (MDR) is a major challenge to the clinical treatment of esophageal cancer. The stress response gene activating transcription factor 4 (ATF4) is involved in homeostasis and cellular protection. However, relatively little is known about the expression and function of ATF4 in esophageal squamous cell carcinoma (ESCC) MDR. In this study, we investigate the potential role and mechanisms of ATF4 in ESCC MDR. We demonstrated that overexpression of ATF4 promotes the MDR phenotype in ESCC cells, while depletion of ATF4 in the MDR ESCC cell line induces drug re-sensitization. We also demonstrated that ATF4 transactivates STAT3 expression by directly binding to the signal transducers and activators of transcription 3 (STAT3) promoter, resulting in MDR in ESCC cells. Significantly, inhibition of STAT3 by small interfering RNA (siRNA) or a selective inhibitor (JSI-124) reintroduces therapeutic sensitivity. In addition, increased Bcl-2, survivin, and MRP1 expression levels were observed in ATF4-overexpressing cells. In conclusion, ATF4 may promote MDR in ESCC cells through the up-regulation of STAT3 expression, and thus is an attractive therapeutic target to combat therapeutic resistance in ESCC.
authors.affiliation: Department of Gastroenterology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Oncology, Fuzhou General Hospital of the Nanjing Military Command of the PLA, Fuzhou, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Oncology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Oncology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Gerontology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
authors.forename: Weibing
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Gastroenterology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Gastroenterology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
authors.forename: Qiuqiong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China. Electronic address: sundayong1967@126.com.
authors.forename: Dayong
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Gastroenterology, Guangzhou General Hospital of the Guangzhou Military Command of the People's Liberation Army (PLA), Guangzhou, China. Electronic address: yagang78@163.com.
authors.forename: Yagang
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D017209:Apoptosis; D063646:Carcinogenesis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077022:Survivin; D015533:Transcriptional Activation
chemical_list: D051701:Activating Transcription Factor 4; D053148:Caspase 3; D051034:Inhibitor of Apoptosis Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D000077022:Survivin; C497109:ATF4 protein, human; C107489:BIRC5 protein, human; C494086:STAT3 protein, human; C505407:CASP3 protein, human; C421109:multidrug resistance-associated protein 1
keywords: Activating transcription factor 4; Esophageal squamous cell carcinoma; Multidrug resistance; Signal transducers and activators of transcription 3