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NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin

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Author(s)
Seung Un SeoTae Hwan KimDong Eun KimKyoung-jin MinTaeg Kyu Kwon
Keimyung Author(s)
Kim, Dong EunKwon, Taeg Kyu
Department
Dept. of Otorhinolaryngology (이비인후과학)
Dept. of Immunology (면역학)
Journal Title
Redox Biology
Issued Date
2017
Volume
13
Keyword
CurcuminMcl-1NOX4Thioridazinec-FLIP
Abstract
Thioridazine is known to have anti-tumor effects by inhibiting PI3K/Akt signaling, which is an important signaling pathway in cell survival. However, thioridazine alone does not induce apoptosis in head and neck squamous cell carcinoma (AMC-HN4), human breast carcinoma (MDA-MB231), and human glioma (U87MG) cells. Therefore, we investigated whether combined treatment with thioridazine and curcumin induces apoptosis. Combined treatment with thioridazine and curcumin markedly induced apoptosis in cancer cells without inducing apoptosis in human normal mesangial cells and human normal umbilical vein cells (EA.hy926). We found that combined treatment with thioridazine and curcumin had synergistic effects in AMC-HN4 cells. Among apoptosis-related proteins, thioridazine plus curcumin induced down-regulation of c-FLIP and Mcl-1 expression at the post-translational levels in a proteasome-dependent manner. Augmentation of proteasome activity was related to the up-regulation of proteasome subunit alpha 5 (PSMA5) expression in curcumin plus thioridazine-treated cells. Combined treatment with curcumin and thioridazine produced intracellular ROS in a NOX4-dependent manner, and ROS-mediated activation of Nrf2/ARE signaling played a critical role in the up-regulation of PSMA5 expression. Furthermore, ectopic expression of c-FLIP and Mcl-1 inhibited apoptosis in thioridazine and curcumin-treated cells. Therefore, we demonstrated that thioridazine plus curcumin induces proteasome activity by up-regulating PSMA5 expression via NOX4-mediated ROS production and that down-regulation of c-FLIP and Mcl-1 expression post-translationally is involved in apoptosis.
Keimyung Author(s)(Kor)
김동은
권택규
Publisher
School of Medicine (의과대학)
Citation
Seung Un Seo et al. (2017). NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin. Redox Biology, 13, 608–622. doi: 10.1016/j.redox.2017.07.017
Type
Article
ISSN
2213-2317
DOI
10.1016/j.redox.2017.07.017
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/41369
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
1. School of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학)
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