Gastroesophageal reflux disease (GERD) and Barrett's esophagus are the major risk factors for esophageal adenocarcinoma, a deadly cancer whose incidence has increased more than 7-fold over the past three decades. For reasons that remain unclear, metaplastic Barrett's cells are predisposed to cancer progression. Although the precise molecular events underlying this malignant transformation are not known, chronic GERD appears to underlie the process, perhaps because GERD causes inflammation with oxidative stress and oxidative DNA damage in Barrett's epithelial cells. The modern medical therapy of GERD is directed almost exclusively at decreasing gastric acid production with medications such as proton pump inhibitors (PPIs). Although the PPIs have been extremely effective for healing reflux esophagitis, these medications do not correct the underlying reflux diathesis, nor do they prevent bile reflux-induced oxidative DNA injury. This might explain why the frequency of esophageal adenocarci-noma continues to rise despite the widespread use of PPIs. Clearly, new medical treatments are needed to prevent bile reflux-induced oxidative stress and the malignant progression of Barrett's metaplasia. Recent data suggest that esophageal adenocarcinomas develop as a consequence of GERD-induced oxidative genomic damage. Left unrepaired, oxidative DNA damage accumulates with subsequent cell cycles, leading to the genomic instability that is a strong predictor for cancer progression in Barrett's metaplasia. Maintenance of genomic integrity requires an appropriate cellular response to oxidative genomic injury, which is a key function of the p53 gene that is inactivated frequently during carcinogenesis in Barrett's esophagus. Oxidative stress and oxidative DNA damage activate Ataxia-Telangiectasia Mutated (ATM), a protein that transmits oxidative damage signals to p53 and p38 effector proteins. Data suggest that, in p53-deficient cells, ATM-induced activation of p38 is essential to cause G1 arrest, a process that prevents cells with damaged DNA from undergoing mitoses that would perpetuate oxidative DNA errors. Thus, agents that enhance this p38-dependent G1 checkpoint response might be used for chemoprevention in Barrett's esophagus. In both p53-intact and p53-deficent Barrett's cells, our preliminary data demonstrate that weakly acidic bile salts induce oxidative DNA damage, cause G1 arrest, and rapidly increase levels of APE-1 and XRCC1 (base excision repair [BER] proteins that correct oxidative damage). Weakly acidic bile salts increase phospho- p38 expression, which appears to be especially important for maintaining genomic integrity in Barrett's metaplasia, as evidenced by our finding that p38 inhibition abolishes the G1 arrest induced by weakly acidic bile salts. In addition, our preliminary data show that ursodeoxycholic acid (UDCA, a non-genotoxic, hydrophilic bile acid) hastens DNA repair in these cells. Those findings suggest a potential chemopreventive role for UDCA in patients with Barrett's esophagus. We hypothesize that, in metaplastic Barrett's epithelial cells, reflux-induced oxidative stress activates the p38 stress pathway to induce G1 arrest and enable repair of oxidative DNA damage, and that treatment with UDCA can enhance these response and repair processes.
The aims of this study are: 1) To elucidate the mechanisms whereby oxidative stress caused by acid and bile salts activates p38 to regulate proteins that control the G1-S cell cycle checkpoint in Barrett's epithelial cells, and to determine if UDCA enhances these responses, 2) To elucidate the role of p38 in activating DNA BER proteins to repair acidic bile salt-induced oxidative DNA damage, and if UDCA enhances the efficiency of oxidative DNA damage repair in Barrett's epithelial cells, and 3) To determine the effects of bile acid-induced oxidative stres on phosphorylating p38 and other key proteins regulating the G1-S cell cycle checkpoint, and to determine if oral UDCA treatment enhances the expression of key BER proteins in biopsy specimens of Barrett's metaplasia already collected from patients who completed our previously funded CSR&D Merit Review study.
Gastroesophageal reflux disease (GERD) and its complication Barrett's esophagus are the major risk factors for esophageal adenocarcinoma, a deadly cancer whose incidence has been rising dramatically. GERD and Barrett's esophagus are common disorders in our Veteran patients, for whom esophageal adenocarcinoma has become the most frequent type of esophageal cancer. Proton pump inhibitors (PPIs), which block gastric acid production, are used to treat GERD and prevent cancer in Barrett's esophagus, but the frequency of esophageal adenocarcinoma continues to rise despite the widespread use of PPIs. This suggests that the reflux of noxious agents other than acid (e.g. bile salts) contributes to carcinogenesis, and this proposal explores how the esophagus can protect itself against those agents. The relevance of this proposal to Veteran's Health is that, by understanding the cellular and molecular events that can prevent Barrett's esophagus from progressing to cancer, we will be able to develop cancer-preventive treatments for our Veteran patients.
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