Fisetin‐induced apoptosis of human oral cancer SCC‐4 cells through reactive oxygen species production,endoplasmic reticulum stress,caspase‐, and mitochondria‐dependent signaling pathways |
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| Authors: | Chen‐Hsuan Su Chao‐Lin Kuo Kung‐Wen Lu Fu‐Shun Yu Yi‐Shih Ma Jiun‐Long Yang Yung‐Lin Chu Fu‐Shin Chueh Kuo‐Ching Liu Jing‐Gung Chung |
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| Affiliation: | 1. Department of Biological Science and Technology, China Medical University, Taichung, Taiwan;2. Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan;3. College of Chinese Medicine, School of Post‐Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan;4. School of Dentistry, China Medical University, Taichung, Taiwan;5. School of Chinese Medicine for Post‐Baccalaureate, I‐Shou University, Kaohsiung, Taiwan;6. Department of Chinese Medicine, E‐Da Hospital, Kaohsiung, Taiwan;7. International Master's Degree Program in Food Science, International College, National Pingtung University of Science and Technology, Pingtung, Taiwan;8. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan;9. Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan;10. Department of Biotechnology, Asia University, Wufeng, Taichung, Taiwan |
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| Abstract: | Oral cancer is one of the cancer‐related diseases in human populations and its incidence rates are rising worldwide. Fisetin, a flavonoid from natural products, has been shown to exhibit anticancer activities in many human cancer cell lines but the molecular mechanism of fisetin‐induced apoptosis in human oral cancer cells is still unclear; thus, in this study, we investigated fisetin‐induced cell death and associated signal pathways on human oral cancer SCC‐4 cells in vitro. We examined cell morphological changes, total viable cells, and cell cycle distribution by phase contrast microscopy and flow cytometry assays. Reactive oxygen species (ROS), Ca2+, mitochondria membrane potential (ΔΨm), and caspase‐8, ‐9, and ‐3 activities were also measured by flow cytometer. Results indicate that fisetin induced cell death through the cell morphological changes, caused G2/M phase arrest, induction of apoptosis, promoted ROS and Ca2+ production, and decreased the level of ΔΨm and increased caspase‐3, ‐8, and ‐9 activities in SCC‐4 cells. DAPI staining and DNA gel electrophoresis were also used to confirm fisetin‐induced cell apoptosis in SCC‐4 cells. Western blotting also found out that Fisetin increased the proapoptotic proteins such as Bax and Bid and decreased the antiapoptotic proteins such as Bcl‐2. Furthermore, results also showed that Fisetin increased the cytochrome c, AIF, and Endo G release from mitochondria in SCC‐4 cells. We also used ATF‐6α, ATF‐6β, GADD153, and GRP78 which indicated that fisetin induced cell death through ER stress. Based on those observations, we suggest that fisetin induced cell apoptosis through ER stress, mitochondria‐, and caspase‐dependent pathways. |
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| Keywords: | apoptosis DNA ladder Fisetin mitochondria SCC‐4 cells |
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