# Elucidating Novel APE1 Redox-Dependent Functions in Esophageal Adenocarcinoma

> **NIH NIH P01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2022 · $414,010

## Abstract

ABSTRACT/SUMMARY
 The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past
three decades. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts abnormally refluxate
into the esophagus, leads to the development of Barrett’s esophagus (BE), a premalignant condition that is the
main risk factor for EAC. We and others have shown that chronic exposure to acidic bile salts induces
inflammation and is associated with a dramatic increase in the burden of oxidative stress; believed to be the
main driving forces for disruption of cellular signaling mechanisms and the development of EAC. It is unknown
how tumorigenic esophageal cells escape the oxidative effects of acidic bile salts reflux and also become
resistant to currently used chemotherapeutic agents. Alterations in the redox status of reactive cysteine
residues, located within the DNA-binding domain of redox-sensitive transcription factors (TFs), can suppress
TFs’ DNA binding affinity and transcription activity. Therefore, the cellular redox capacity is paramount in
promoting activity of oncogenic transcription factors, protecting tumorigenic cells and promoting their survival
and expansion. This project builds upon collective interaction among the three projects generating several
novel preliminary findings. We have shown that AP endonuclease 1 (APE1) redox activity was required for
activation of tumorigenic transcription factors such as SOX9 in response to exposure to reflux and
chemotherapeutics. As part of scientific integration in this P01, working with Projects 2 and 3, we also found
that high levels of reactive isolevuglandins (isoLGs) protein adducts promote stability of SOX9. As a result of
these molecular events, EACs develop intrinsic and acquired resistance to standard chemotherapeutic. Based
on our preliminary results, we aim to investigate the role of APE1-reodx function in promoting SOX9 activation
in EACs. In Aim 1, we will investigate the role of APE1 and isoLG adducts in regulating SOX9 stability and
activity. The functional outcome of APE1-SOX9 network is investigated in Aim 2. The clinical significance and
therapeutic potential of targeting APE1 redox activity will be determined in Aim 3. Understanding biology-
relevant molecular functions, the focus of this P01 and this project, is a key step for developing evidence-
based therapeutic approaches that are founded on the biology and molecular underpinning of EAC. Upon
completion of our work, we expect to uncover a new paradigm for understanding the biology of EAC to
facilitate the development of novel medical treatments for this deadly cancer.

## Key facts

- **NIH application ID:** 10407745
- **Project number:** 1P01CA268991-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** WAEL EL-RIFAI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $414,010
- **Award type:** 1
- **Project period:** 2022-07-08 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407745

## Citation

> US National Institutes of Health, RePORTER application 10407745, Elucidating Novel APE1 Redox-Dependent Functions in Esophageal Adenocarcinoma (1P01CA268991-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10407745. Licensed CC0.

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