Acidic bile salts induce APE1-dependent PRDX2 activation to drive oxaliplatin resistance via ferroptosis inhibition

The incidence of esophageal adenocarcinoma (EAC) is rapidly increasing in Western countries. Gastroesophageal reflux, containing acidic bile salts (ABS), is the main risk factor for EAC. Cancer cells develop adaptive abilities to recalibrate redox balance via hijacking the antioxidant systems to maintain reactive oxygen species (ROS) below lethal levels. We investigated the role of PRDX2 and its regulation in EAC chemoresistance under reflux conditions.

We analyzed public databases to identify PRDX2's aberrant overexpression and potential role in chemoresistance in EAC. To model acute and chronic GERD in vitro, we applied transient and repeated ABS exposures. Using 2D and 3D organotypic culture models of EAC cells, we investigated PRDX2's anti-ferroptosis, pro-chemoresistance functions, and regulatory mechanisms. In addition, we also utilized patient derived organoids and xenografts, cell line-derived xenografts, and human EAC tissue microarrays.

Aberrant expression of PRDX2 was detected in both human EAC tissues and cell lines under ABS exposure. PRDX2 was regulated via an APE1-redox-dependent transcription activation of NF-kB. The knockdown of PRDX2 impaired the recovery of EAC cells from ABS-induced ROS and ROS-dependent lipid peroxidation. Silencing PRDX2 sensitized the chemo-resistant EAC cells to oxaliplatin by enhancing ferroptosis. Mechanistically, we found that PRDX2 inhibits ferroptosis by stabilizing GPX4, a crucial ferroptosis suppressor. PRDX2 enhances GPX4 stability through OTUB1-dependent deubiquitination, preventing its degradation. The APE1-redox inhibitor APX2009 significantly sensitized EAC cells to oxaliplatin by downregulating PRDX2 and inducing ferroptosis. Importantly, the combination of oxaliplatin and APX2009 showed synergistic tumor-suppressive effects in xenograft models.

Our findings revealed a novel link between reflux-induced redox rebalance and ferroptosis-related chemoresistance in EAC via APE1-redox/NF-kB/PRDX2/OUTB1/GPX4 signaling cascade. Targeting redox with APE1-redox-specific inhibitors is a potential novel strategy for drug combination in refractory EAC, via inhibition of PRDX2.