Regulation of esophageal tumorigenesis by protein adduction

SUMMARY
Esophageal adenocarcinoma (EAC) is the most prevalent histological type of esophageal malignancy in the US
and many Western nations. This tumor remains deadly as approximately 80% of patients are diagnosed at
advanced stages and have a low five-year survival rate. Gastroesophageal reflux disease (GERD) is one of the
strongest risk factors for EAC. In GERD patients, the epithelial lining of the esophagus is exposed to the
gastroesophageal reflux (GER) that contains gastric acid frequently mixed with duodenal bile. The esophageal
epithelial cells undergoes severe damage from exposure to acid and bile salts. This exposure also promotes
inflammation, which can exacerbate tissue damage and lead to the development of Barrett's esophagus (BE).
BE is a preneoplastic condition that is disposed to malignant transformation. The molecular mechanisms of
esophageal tumorigenesis in conditions of esophageal reflux injury remain poorly understood. We have
developed an innovative hypothesis to investigate how isolevuglandin (isoLG) lipid derivatives that adduct
multiple proteins in conditions of esophageal reflux facilitate tumorigenic processes by protein adduction. IsoLGs
are formed from the free radicals induced peroxidation of lipids and cyclooxygenase (COX) and are highly
reactive for lysine as well as other cellular amines. IsoLGs bind covalently with the protein molecules to inflict
damage before being recognized by cellular defense mechanisms. In our experimental conditions of esophageal
reflux, p63 is found to be one of the most adducted proteins by isoLGs. P63 is a master regulator of esophageal
epithelial development, which also regulate a broad spectrum of genes involved in different cellular processes
such as DNA repair, stemness, proliferation and differentiation. Our preliminary data strongly support the
hypothesis by providing evidence of the alteration of p63 protein by adduction. In aim 1, using in vitro cell
systems, this proposal will examine the unique mechanisms regulating p63 signaling pathway by protein
adduction and its biological impact in conditions of esophageal reflux injury. In aim 2, we will study the p63
protein adduction in in vivo mice model and test various pharmacological options to reverse this process. If
successful, this study will provide a new therapeutic approach to prevent the pro-tumorigenic alterations of
esophageal cancer.

Grant Number: 5R03CA286671-02
NIH Institute/Center: NIH
Principal Investigator: Ravindran Caspa Gokulan