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.
['Na|Yoo Jin|YJ|', 'Lee|Dae-Hee|DH|', 'Kim|Jung Lim|JL|', 'Kim|Bo Ram|BR|', 'Park|Seong Hye|SH|', 'Jo|Min Jee|MJ|', 'Jeong|Soyeon|S|', 'Kim|Hong Jun|HJ|', 'Lee|Suk-Young|SY|', 'Jeong|Yoon A|YA|', 'Oh|Sang Cheul|SC|']
D017209:Apoptosis D045744:Cell Line, Tumor D019008:Drug Resistance, Neoplasm D004357:Drug Synergism D059865:Endoplasmic Reticulum Stress D015972:Gene Expression Regulation, Neoplastic D006801:Humans D051034:Inhibitor of Apoptosis Proteins D046988:Proteasome Endopeptidase Complex D059748:Proteolysis D017382:Reactive Oxygen Species D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand D013274:Stomach Neoplasms D000077022:Survivin D053221:TNF-Related Apoptosis-Inducing Ligand D051742:Transcription Factor CHOP D015854:Up-Regulation D014704:Veratrum Alkaloids
Cyclopamine TRAIL-resistance Death receptor 5 Survivin CHOP