title: Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-κB activation in benign Barrett's epithelial cells.
abstract: Gastroesophageal reflux is associated with adenocarcinoma in Barrett's esophagus, but the incidence of this tumor is rising, despite widespread use of acid-suppressing medications. This suggests that refluxed material other than acid might contribute to carcinogenesis. We looked for potentially carcinogenetic effects of two bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on Barrett's epithelial cells in vitro and in vivo. We exposed Barrett's (BAR-T) cells to DCA or UDCA and studied the generation of reactive oxygen/nitrogen species (ROS/RNS); expression of phosphorylated H2AX (a marker of DNA damage), phosphorylated IkBα, and phosphorylated p65 (activated NF-κB pathway proteins); and apoptosis. During endoscopy in patients, we took biopsy specimens of Barrett's mucosa before and after esophageal perfusion with DCA or UDCA and assessed DNA damage and NF-κB activation. Exposure to DCA, but not UDCA, resulted in ROS/RNS production, DNA damage, and NF-κB activation but did not increase the rate of apoptosis in BAR-T cells. Pretreatment with N-acetyl-l-cysteine (a ROS scavenger) prevented DNA damage after DCA exposure, and DCA did induce apoptosis in cells treated with NF-κB inhibitors (BAY 11-7085 or AdIκB superrepressor). DNA damage and NF-κB activation were detected in biopsy specimens of Barrett's mucosa taken after esophageal perfusion with DCA, but not UDCA. These data show that, in Barrett's epithelial cells, DCA induces ROS/RNS production, which causes genotoxic injury, and simultaneously induces activation of the NF-κB pathway, which enables cells with DNA damage to resist apoptosis. We have demonstrated molecular mechanisms whereby bile reflux might contribute to carcinogenesis in Barrett's esophagus.
authors.affiliation: Department of Medicine, Veterans Affairs North Texas Health Care System, Children’s Medical Center, USA.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Huo
authors.forename: Stefanie
authors.initials: S
authors.lastname: Juergens
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.forename: Davood
authors.initials: D
authors.lastname: Rezaei
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yu
authors.forename: Eric D
authors.initials: ED
authors.lastname: Strauch
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Wang
authors.forename: Edaire
authors.initials: E
authors.lastname: Cheng
authors.forename: Frank
authors.initials: F
authors.lastname: Meyer
authors.forename: David H
authors.initials: DH
authors.lastname: Wang
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Spechler
authors.forename: Rhonda F
authors.initials: RF
authors.lastname: Souza
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001471:Barrett Esophagus / Q000378:metabolism*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage / Q000187:drug effects; D003840:Deoxycholic Acid / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D003840:Deoxycholic Acid; D000072000:NF-KappaB Inhibitor alpha; D014580:Ursodeoxycholic Acid