TY - JOUR
T1 - The antioxidant response in Barrett's tumorigenesis
T2 - A double-edged sword
AU - Peng, Dunfa
AU - Zaika, Alexander
AU - Que, Jianwen
AU - El-Rifai, Wael
N1 - Funding Information:
The research reported in this publication was supported by grants from the National Cancer Institute ( R01CA224366 ) and the U.S. Department of Veterans Affair ( 1IK6BX003787 and I01BX001179 ). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Veterans Affairs, National Institutes of Health, or the University of Miami.
Funding Information:
The research reported in this publication was supported by grants from the National Cancer Institute (R01CA224366) and the U.S. Department of Veterans Affair (1IK6BX003787 and I01BX001179). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Veterans Affairs, National Institutes of Health, or the University of Miami.
Publisher Copyright:
© 2021 The Authors
PY - 2021/5
Y1 - 2021/5
N2 - Esophageal adenocarcinoma (EAC) is the dominant form of esophageal malignancies in the United States and other industrialized countries. The incidence of EAC has been rising rapidly during the past four decades. Barrett's esophagus (BE) is the main precancerous condition for EAC, where a metaplastic columnar epithelium replaces normal squamous mucosa of the lower esophagus. The primary risk factor for BE and EAC are chronic gastroesophageal reflux disease (GERD), obesity and smoking. During the BE-dysplasia-EAC sequence, esophageal cells are under a tremendous burden of accumulating reactive oxygen species (ROS) and oxidative stress. While normal cells have intact antioxidant machinery to maintain a balanced anti-tumorigenic physiological response, the antioxidant capacity is compromised in neoplastic cells with a pro-tumorigenic development antioxidant response. The accumulation of ROS, during the neoplastic progression of the GERD-BE-EAC sequence, induces DNA damage, lipid peroxidation and protein oxidation. Neoplastic cells adapt to oxidative stress by developing a pro-tumorigenic antioxidant response that keeps oxidative damage below lethal levels while promoting tumorigenesis, progression, and resistance to therapy. In this review, we will summarize the recent findings on oxidative stress in tumorigenesis in the context of the GERD-BE-EAC process. We will discuss how EAC cells adapt to increased ROS. We will review APE1 and NRF2 signaling mechanisms in the context of EAC. Finally, we will discuss the potential clinical significance of applying antioxidants or NRF2 activators as chemoprevention and NRF2 inhibitors in treating EAC patients.
AB - Esophageal adenocarcinoma (EAC) is the dominant form of esophageal malignancies in the United States and other industrialized countries. The incidence of EAC has been rising rapidly during the past four decades. Barrett's esophagus (BE) is the main precancerous condition for EAC, where a metaplastic columnar epithelium replaces normal squamous mucosa of the lower esophagus. The primary risk factor for BE and EAC are chronic gastroesophageal reflux disease (GERD), obesity and smoking. During the BE-dysplasia-EAC sequence, esophageal cells are under a tremendous burden of accumulating reactive oxygen species (ROS) and oxidative stress. While normal cells have intact antioxidant machinery to maintain a balanced anti-tumorigenic physiological response, the antioxidant capacity is compromised in neoplastic cells with a pro-tumorigenic development antioxidant response. The accumulation of ROS, during the neoplastic progression of the GERD-BE-EAC sequence, induces DNA damage, lipid peroxidation and protein oxidation. Neoplastic cells adapt to oxidative stress by developing a pro-tumorigenic antioxidant response that keeps oxidative damage below lethal levels while promoting tumorigenesis, progression, and resistance to therapy. In this review, we will summarize the recent findings on oxidative stress in tumorigenesis in the context of the GERD-BE-EAC process. We will discuss how EAC cells adapt to increased ROS. We will review APE1 and NRF2 signaling mechanisms in the context of EAC. Finally, we will discuss the potential clinical significance of applying antioxidants or NRF2 activators as chemoprevention and NRF2 inhibitors in treating EAC patients.
KW - APE1
KW - Antioxidant response
KW - Barrett's esophagus
KW - Esophageal adenocarcinoma
KW - NRF2
KW - Oxidative stress
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U2 - 10.1016/j.redox.2021.101894
DO - 10.1016/j.redox.2021.101894
M3 - Review article
AN - SCOPUS:85101092639
VL - 41
JO - Redox Biology
JF - Redox Biology
SN - 2213-2317
M1 - 101894
ER -