title: Proton pump inhibitors (PPIs) impact on tumour cell survival, metastatic potential and chemotherapy resistance, and affect expression of resistance-relevant miRNAs in esophageal cancer.
abstract: BACKGROUND
  Neoadjuvant treatment plays a crucial role in the therapy of advanced esophageal cancer. However, response to radiochemotherapy varies widely. Proton pump inhibitors (PPIs) have been demonstrated to impact on chemotherapy in a variety of other cancers. We analyzed the impact of PPI treatment on esophageal cancer cell lines, and investigated mechanisms that mediate the effect of PPI treatment in this tumour.
  
  
  METHODS
  We investigated the effect of esomeprazole treatment on cancer cell survival, adhesion, migration and chemotherapy in human adeno-(OE19) and squamous-cell-carcinoma (KYSE410) cell lines. Furthermore, we investigated the effect of PPI treatment on intra-/extracellular pH and on expression of resistance-relevant miRNAs.
  
  
  RESULTS
  Esomeprazole significantly inhibited tumour cell survival (in a dose-dependent manner), adhesion and migration in both tumour subtypes. Furthermore, esomeprazole augmented the cytotoxic effect of cisplatin and 5-FU in both tumour subtypes. Surprisingly, PPI treatment led to a significant increase of intracellular pH and a decrease of the extracellular pH. Finally, we found esomeprazole affected expression of resistance-relevant miRNAs. Specifically, miR-141 and miR-200b were upregulated, whereas miR-376a was downregulated after PPI treatment in both tumour types.
  
  
  CONCLUSIONS
  Our study demonstrates for the first time that PPIs impact on tumour cell survival, metastatic potential and sensitivity towards chemotherapy in esophageal cancer cell lines. Furthermore, we observed that in this tumour entity, PPIs do not lead to intracellular acidification, but affect the expression of resistance-relevant miRNAs.
authors.affiliation: Department of General and Visceral Surgery, Muenster University Hospital, Waldeyerstr. 1, 48149, Muenster, Germany. kirsten.lindner@ukmuenster.de.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Lindner
authors.affiliation: Department of General and Visceral Surgery, Muenster University Hospital, Waldeyerstr. 1, 48149, Muenster, Germany. ch.borchardt@uni-muenster.de.
authors.forename: Christiane
authors.initials: C
authors.lastname: Borchardt
authors.affiliation: Department of General and Visceral Surgery, Muenster University Hospital, Waldeyerstr. 1, 48149, Muenster, Germany. maren.schoepp@ukmuenster.de.
authors.forename: Maren
authors.initials: M
authors.lastname: Schöpp
authors.affiliation: Department of General and Visceral Surgery, Muenster University Hospital, Waldeyerstr. 1, 48149, Muenster, Germany. anja.buergers@uni-muenster.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Bürgers
authors.affiliation: Institute of Physiology, University of Muenster, Muenster, Germany. cmstock@uni-muenster.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Stock
authors.affiliation: Department of Surgery, Flinders Medical Centre, Flinders University, Adelaide, Australia. damian.hussey@flinders.edu.au.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Hussey
authors.affiliation: Comprehensive Cancer Centre, University of Muenster, Muenster, Germany. joerg.haier@ukmuenster.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Haier
authors.affiliation: Department of General and Visceral Surgery, Muenster University Hospital, Waldeyerstr. 1, 48149, Muenster, Germany. richard.hummel@ukmuenster.de.
authors.forename: Richard
authors.initials: R
authors.lastname: Hummel
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D064098:Esomeprazole / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006863:Hydrogen-Ion Concentration; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D054328:Proton Pump Inhibitors / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human; C573498:MIRN376C microRNA, human; D035683:MicroRNAs; D054328:Proton Pump Inhibitors; D064098:Esomeprazole; D002945:Cisplatin; D005472:Fluorouracil