Journal
MOLECULAR CARCINOGENESIS
Volume 55, Issue 11, Pages 1526-1541Publisher
WILEY
DOI: 10.1002/mc.22406
Keywords
Barrett's esophagus; autophagy; oxidative stress; esophageal adenocarcinoma; chloroquine
Categories
Funding
- NCI BETRNet program [CA163004 JPL]
- Integrated Microphysiological Systems [TR 000536]
- NIH [OD 012097]
- University of Pennsylvania Transdisciplinary Research
- Morphology, Cell Culture, and Molecular Biology Core Facilities of the Center [P30-DK050306 PO1 CA098101]
- [K26 RR 032714]
- [K01DK103953]
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Autophagy is a highly conserved mechanism that is activated during cellular stress. We hypothesized that autophagy may be induced by acid reflux, which causes injury, and inflammation, and therefore, contributes to the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Currently, the role of autophagy in BE and EAC is poorly studied. We quantitatively define autophagy levels in human BE cell lines, a transgenic mouse model of BE, and human BE, and EAC biopsies. Human non-dysplastic BE had the highest basal number of autophagic vesicles (AVs), while AVs were reduced in normal squamous cells and dysplastic BE cells, and nearly absent in EAC. To demonstrate a functional role for autophagy in BE pathogenesis, normal squamous (STR), non-dysplastic BE (CPA), dysplastic BE (CPD), and EAC (OE19) cell lines were exposed to an acid pulse (pH 3.5) followed by incubation in the presence or absence of chloroquine, an autophagy inhibitor. Acid exposure increased reactive oxygen species (ROS) levels in STR and CPA cells. Chloroquine alone had a small impact on intracellular ROS or cell survival. However, combination of chloroquine with the acid pulse resulted in a significant increase in ROS levels at 6 h in STR and CPA cells, and increased cell death in all cell lines. These findings establish increased numbers of AVs in human BE compared to normal squamous or EAC, and suggest that autophagy functions to improve cell survival after acid reflux injury. Autophagy may thus play a critical role in BE pathogenesis and progression. (C) 2015 Wiley Periodicals, Inc.
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