title: Proton pump inhibitor pantoprazole abrogates adriamycin-resistant gastric cancer cell invasiveness via suppression of Akt/GSK-β/β-catenin signaling and epithelial-mesenchymal transition.
abstract: The effect of proton pump inhibitor (PPI) on cancer risk has received much attention recently. In this study, we investigated the mechanism underlying multidrug resistance and the effect of a PPI pantoprazole using an adriamycin-resistant gastric cancer cell model (SGC7901/ADR). Compared with the parental cell line, SGC7901/ADR cells showed reduced proliferation rate, but higher resistance to adriamycin under both anchorage-dependent and -independent conditions. Notably, SGC7901/ADR cells underwent epithelial to mesenchymal transition (EMT) and showed increased migrating and invading capabilities. At molecular level, SGC7901/ADR cells showed strong activation of Wnt/β-catenin signaling pathway compared with parental sensitive cells. Interestingly, we found that a PPI pantoprazole can effectively reverse the aggressiveness and EMT marker expression of SGC7901/ADR cells. Furthermore, pantoprazole treatment resulted in a profound reduction of both total and phosphorylated forms of Akt and GSK-3β, which in turn suppressed the adriamycin-induced Wnt/β-catenin signaling in SGC7901/ADR cells. Taken together, we demonstrate that the aggressive phenotype of adriamycin-resistant SGC7901/ADR cells is mediated by induction of EMT and activation of the canonical Wnt/β-catenin signaling pathway. And for the first time, we show that it is possible to suppress the invasiveness of SGC7901/ADR cells by pantoprazole which targets the EMT and Akt/GSK-3β/β-catenin signaling.
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China; State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, Jiangsu Province, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Wanyu
authors.initials: W
authors.lastname: Liao
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: School of Biomedical Sciences and State Key Laboratory of Digestive Disease, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Alfred Sze-Lok
authors.initials: AS
authors.lastname: Cheng
authors.affiliation: Department of Laboratory Diagnostic, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Fang
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Shuling
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Guangxia
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Tingsheng
authors.initials: T
authors.lastname: Ling
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China.
authors.forename: Yuzheng
authors.initials: Y
authors.lastname: Zhuge
authors.affiliation: Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu Province, China; State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, Jiangsu Province, China. Electronic address: zouxiaoping795@hotmail.com.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zou
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009361:Neoplasm Invasiveness; D000077402:Pantoprazole; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000903:Antibiotics, Antineoplastic; D054328:Proton Pump Inhibitors; D012333:RNA, Messenger; D004317:Doxorubicin; D000077402:Pantoprazole; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Drug resistance; Epithelial to mesenchymal transition; Invasiveness; Pantoprazole