title: Activating transcription factor 4 increases chemotherapeutics resistance of human hepatocellular carcinoma.
abstract: It has been reported that activating transcription factor 4 (ATF4) increases the processes of tumor growth, metastasis and drug resistance. However, the role played by ATF4 in chemoresistance of hepatocellular carcinoma (HCC) remains unknown. Clarification of this role of ATF4 in HCC could greatly benefit the efficacy of clinical treatment of HCC. In this study, we found that ATF4 was overexpressed in about 50.7% of HCC tissues. In fact knockdown of ATF4 significantly increased the cytotoxicity of cisplatin in both in vitro and in vivo assays, while overexpression of this molecule dramatically decreased the sensitivity of HCC cell lines to cisplatin. Additionally, we found that synthesis of glutathione was significantly reduced in HCC cell lines subjected to ATF4 knockdown. Taken together, these results demonstrate that ATF4 can increase resistance to cisplatin in HCC by increased biosynthesis of glutathione, and that this may be a potent novel target for the future development of anti-HCC drugs.
authors.affiliation: Department of Immunology, The School of Medicine, Nankai University, Tianjin, China.
authors.forename: Zhuhong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Yin
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Liang
authors.forename: Nan
authors.initials: N
authors.lastname: Bai
authors.forename: Antao
authors.initials: A
authors.lastname: Chang
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Liu
authors.forename: Zongjin
authors.initials: Z
authors.lastname: Li
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Tan
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: Lv
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Yaping
authors.initials: Y
authors.lastname: Tian
authors.forename: Chenghu
authors.initials: C
authors.lastname: Liu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D012016:Reference Values; D023041:Xenograft Model Antitumor Assays
chemical_list: C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D051701:Activating Transcription Factor 4; D005978:Glutathione; D002945:Cisplatin