Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells

Cancers

Boris Jansen-Winkeln¹  René Thieme¹  Orestis Lyros¹  Ines Gockel¹  Olga Chemnitzer¹  Yusef Moulla¹  Lucie Storz¹  Philipp Walther¹  Stefan Niebisch¹  Matthias Mehdorn¹  Thomas Büch² 

[1] Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany;Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Haertelstrasse 16–18, 04103 Leipzig, Germany;

关键词: Barrett’s esophagus;    esophageal adenocarcinoma;    chemotherapy;    gastroesophageal reflux disease (GERD);    inflammation;   

DOI  :  10.3390/cancers13112806

来源: DOAJ

【 摘 要 】

Chronic acid reflux causes cellular damage and inflammation in the lower esophagus. Due to these irritating insults, the squamous epithelium is replaced by metaplastic epithelium, which is a risk factor for the development of esophageal adenocarcinoma (EAC). In this study, we investigated the acid susceptibility in a Barrett’s cell culture in vitro model, using six cell lines, derived from squamous epithelium (EPC1 and EPC2), metaplasia (CP-A), dysplasia (CP-B), and EAC (OE33 and OE19) cells. Cells exposed to acidic pH showed a decreased viability dependent on time, pH, and progression status in the Barrett’s sequence, with the highest acid susceptibility in the squamous epithelium (EPC1 and EPC2), and the lowest in EAC cells. Acid pulsing was accompanied with an activation of the Nrf2/Keap1- and the NFκB-pathway, resulting in an increased expression of HO1—independent of the cellular context. OE33 showed a decreased responsiveness towards 5-FU, when the cells were grown in acidic conditions (pH 6 and pH 5.5). Our findings suggest a strong damage of squamous epithelium by gastroesophageal reflux, while Barrett’s dysplasia and EAC cells apparently exert acid-protective features, which lead to a cellular resistance against acid reflux.

【 授权许可】

Unknown