Activation of NADPH oxidases leads to DNA damage in esophageal cells

Vikas Bhardwaj, Ravindran Caspa Gokulan, Andela Horvat, Liudmila Yermalitskaya, Olga Korolkova, Kay M. Washington, Wael El-Rifai, Sergey I. Dikalov, Alexander Zaika

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Gastroesophageal reflux disease (GERD) is the strongest known risk factor for esophageal adenocarcinoma. In the center of tumorigenic events caused by GERD is repeated damage of esophageal tissues by the refluxate. In this study, we focused on a genotoxic aspect of exposure of esophageal cells to acidic bile reflux (BA/A). Analyzing cells generated from patients with Barrett's esophagus and human esophageal specimens, we found that BA/A cause significant DNA damage that is mediated by reactive-oxygen species. ROS originate from mitochondria and NADPH oxidases. We specifically identified NOX1 and NOX2 enzymes to be responsible for ROS generation. Inhibition of NOX2 and NOX1 with siRNA or chemical inhibitors significantly suppresses ROS production and DNA damage induced by BA/A. Mechanistically, our data showed that exposure of esophageal cells to acidic bile salts induces phosphorylation of the p47phox subunit of NOX2 and its translocation to the cellular membrane. This process is mediated by protein kinase C, which is activated by BA/A. Taken together, our studies suggest that inhibition of ROS induced by reflux can be a useful strategy for preventing DNA damage and decreasing the risk of tumorigenic transformation caused by GERD.

Original languageEnglish (US)
Article number9956
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

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NADPH Oxidase
Gastroesophageal Reflux
DNA Damage
Neoplastic Cell Transformation
Bile Reflux
Barrett Esophagus
Bile Acids and Salts
Protein Kinase C
Small Interfering RNA
Reactive Oxygen Species
Mitochondria
Adenocarcinoma
Phosphorylation
Membranes
Enzymes

ASJC Scopus subject areas

  • General

Cite this

Activation of NADPH oxidases leads to DNA damage in esophageal cells. / Bhardwaj, Vikas; Caspa Gokulan, Ravindran; Horvat, Andela; Yermalitskaya, Liudmila; Korolkova, Olga; Washington, Kay M.; El-Rifai, Wael; Dikalov, Sergey I.; Zaika, Alexander.

In: Scientific Reports, Vol. 7, No. 1, 9956, 01.12.2017.

Research output: Contribution to journalArticle

Bhardwaj, V, Caspa Gokulan, R, Horvat, A, Yermalitskaya, L, Korolkova, O, Washington, KM, El-Rifai, W, Dikalov, SI & Zaika, A 2017, 'Activation of NADPH oxidases leads to DNA damage in esophageal cells', Scientific Reports, vol. 7, no. 1, 9956. https://doi.org/10.1038/s41598-017-09620-4
Bhardwaj V, Caspa Gokulan R, Horvat A, Yermalitskaya L, Korolkova O, Washington KM et al. Activation of NADPH oxidases leads to DNA damage in esophageal cells. Scientific Reports. 2017 Dec 1;7(1). 9956. https://doi.org/10.1038/s41598-017-09620-4
Bhardwaj, Vikas ; Caspa Gokulan, Ravindran ; Horvat, Andela ; Yermalitskaya, Liudmila ; Korolkova, Olga ; Washington, Kay M. ; El-Rifai, Wael ; Dikalov, Sergey I. ; Zaika, Alexander. / Activation of NADPH oxidases leads to DNA damage in esophageal cells. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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