title: APE1-mediated DNA damage repair provides survival advantage for esophageal adenocarcinoma cells in response to acidic bile salts.
abstract: Chronic Gastroesophageal Reflux Disease (GERD) is the main risk factor for the development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC). Accordingly, EAC cells are subjected to high levels of oxidative stress and subsequent DNA damage. In this study, we investigated the expression and role of Apurinic/apyrimidinic endonuclease 1 (APE1) protein in promoting cancer cell survival by counteracting the lethal effects of acidic bile salts (ABS)-induced DNA damage. Immunohistochemistry analysis of human tissue samples demonstrated overexpression of APE1 in more than half of EACs (70 of 130), as compared to normal esophagus and non-dysplastic BE samples (P < 0.01). To mimic in vivo conditions, we treated in vitro cell models with a cocktail of ABS. The knockdown of endogenous APE1 in EAC FLO-1 cells significantly increased oxidative DNA damage (P < 0.01) and DNA single- and double-strand breaks (P < 0.01), whereas overexpression of APE1 in EAC OE33 cells reversed these effects. Annexin V/PI staining indicated that the APE1 expression in OE33 cells protects against ABS-induced apoptosis. In contrast, knockdown of endogenous APE1 in FLO-1 cells increased apoptosis under the same conditions. Mechanistic investigations indicated that the pro-survival function of APE1 was associated with the regulation of stress response c-Jun N-terminal protein kinase (JNK) and p38 kinases. Pharmacological inhibition of APE1 base excision repair (BER) function decreased cell survival and enhanced activation of JNK and p38 kinases by ABS. Our findings suggest that constitutive overexpression of APE1 in EAC may be an adaptive pro-survival mechanism that protects against the genotoxic lethal effects of bile reflux episodes.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Dunfa
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaika
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Revetta
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Abbes
authors.initials: A
authors.lastname: Belkhiri
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D001471:Barrett Esophagus / Q000209:etiology / Q000378:metabolism; D001647:Bile Acids and Salts / Q000009:adverse effects*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005764:Gastroesophageal Reflux / Q000150:complications / Q000378:metabolism; D006801:Humans
chemical_list: D001647:Bile Acids and Salts; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APE1; JNK; acidic bile salts; base excision repair; p38