Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the most effective cancer treatments owing to its ability to selectively kill cancer cells, without affecting normal cells. However, it has been reported that several gastric cancer cells show resistance to TRAIL because of a scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we show that cyclopamine sensitizes gastric cancer cells to TRAIL-induced apoptosis by elevating the expression of DR5. Interestingly, survivin hampers the existence of DR5 protein under normal conditions and cyclopamine decreases the expression of survivin, thus acting as a TRAIL sensitizer. Mechanistically, cyclopamine induces endoplasmic reticulum (ER) stress via reactive oxygen species (ROS) and CHOP, the last protein of the ER stress pathway and it regulates the proteasome degradation of survivin. Taken together, our results indicate that cyclopamine can be used for combination therapy in TRAIL-resistant gastric cancer cells.