Esophageal cancer cells convert the death signal from TRAIL into a stimulus for survival during acid/bile exposure

TRAIL is best known for killing cancer cells selectively, however, some cancers resist TRAIL treatment for various reasons. Esophageal adenocarcinoma is such an example. Previously, we reported that the tumor cells interrupted TRAIL-mediated apoptosis by overexpressing the decoy receptors and survivin. To investigate TRAIL resistance in esophageal adenocarcinoma during GERD. We simulated GERD episodes in vitro by exposing cancer cells to the acid/bile conditions acutely as well as chronically. TRAIL and its receptors were examined for expression, interaction, and induction of cell death. We found that acid/bile exposure drove the tumor cells to express TRAIL and TRAILR2 robustly, but did not lead to apoptosis, because the tumor cells overexpressed TRADD to replace FADD as the adaptor molecule to trigger NFκB activation instead of caspases, and thereby convert a death signal from TRAIL into a stimulus for survival. The tumor cells also overexpressed c-FLIP to keep caspases away from TRAILR2 in case FADD finds a way back to the death receptor. Multiple reasons contribute to TRAIL resistance in esophageal adenocarcinoma, including overexpression of the decoy receptors to block the death receptors, using TRADD to replace FADD, and using c-FLIP to replace caspase-8.