@article { author = {Visitnonthachai, Daranee and Nakareangrit, Watanyoo and Suntararuks, Sumitra and Chaiyot, Karnjana and Watcharasit, Piyajit and Satayavivad, Jutamaad}, title = {Potentiation of TRAIL-Induced Apoptosis in TRAIL-Resistant Cholangiocarcinoma Cells by Curcumin through the Induction of DR5 Membrane Localization and Disruption of the Anti-Apoptotic Complex DR5/DDX3/GSK3β}, journal = {Asian Pacific Journal of Cancer Prevention}, volume = {24}, number = {2}, pages = {425-434}, year = {2023}, publisher = {West Asia Organization for Cancer Prevention (WAOCP), APOCP's West Asia Chapter.}, issn = {1513-7368}, eissn = {2476-762X}, doi = {10.31557/APJCP.2023.24.2.425}, abstract = {Objective: Cholangiocarcinoma (CCA) is a cancer of the bile duct with a poor prognosis. The present study examined the ability of curcumin to sensitize apoptosis in the TNF-related apoptosis-inducing ligand (TRAIL)-resistant CCA cell lines of HuCCA-1 and KKU-213A. Methods: Apoptosis was measured using a TUNEL assay. Protein expression was determined by immunoblotting. Membrane death receptor 5 (DR5) was detected by flow cytometry. Protein complex was examined by co-immunoprecipitation. Result: Curcumin potentiated TRAIL-induced apoptosis in both cell lines, indicating the sensitization to TRAIL-induced apoptosis by curcumin. Additionally, curcumin increased DR5 expression and membrane localization; however, the curcumin/TRAIL combination did not result in further increases in DR5 expression and membrane localization in either cell line. Moreover, the curcumin/TRAIL combination reduced DR5/decoy receptor 2 (DcR2) complexes in both cell lines, suggesting that curcumin may enhance TRAIL-induced apoptosis by disrupting DR5/DcR2 interaction. In addition, levels of the anti-apoptotic complex DR5/ DDX3/GSK3β were reduced by the curcumin/TRAIL combination in HuCCA-1 but not in KKU-213A cells. This study also demonstrated that the DR5/DcR2 and DR5/DDX3/GSK3β complexes could be observed under basal conditions, suggesting that these anti-apoptotic complexes may contribute to TRAIL-resistant phenotypes in both cell lines. Pretreatment with the antioxidant N-acetylcysteine attenuated curcumin-enhanced apoptosis by TRAIL, indicating that curcumin sensitized TRAIL-induced apoptosis through an oxidative stress–dependent mechanism. Conclusion: The present study demonstrates the potential of using curcumin in combination with TRAIL to yield better TRAIL therapy outcomes in TRAIL-resistant CCA.}, keywords = {cholangiocarcinoma,curcumin,TRAIL,death receptor 5 (DR5),decoy receptor 2 (DcR2)}, url = {https://journal.waocp.org/article_90513.html}, eprint = {https://journal.waocp.org/article_90513_3f77856813ce10c7dcb946d42d08649e.pdf} }