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Environ Toxicol. 2017 Jun;32(6):1725-1741. doi: 10.1002/tox.22396. Epub 2017 Feb 9.

Fisetin-induced apoptosis of human oral cancer SCC-4 cells through reactive oxygen species production, endoplasmic reticulum stress, caspase-, and mitochondria-dependent signaling pathways.

Author information

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, 404, Taiwan.
3
College of Chinese Medicine, School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, 404, Taiwan.
4
School of Dentistry, China Medical University, Taichung, 404, Taiwan.
5
School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, 84001, Taiwan.
6
Department of Chinese Medicine, E-Da Hospital, Kaohsiung, 82445, Taiwan.
7
International Master's Degree Program in Food Science, International College, National Pingtung University of Science and Technology, Pingtung, 91201, Taiwan.
8
Department of Health and Nutrition Biotechnology, Asia University, Taichung, 413, Taiwan.
9
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
10
Department of Biotechnology, Asia University, Wufeng, Taichung, Taiwan.

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.

KEYWORDS:

DNA ladder; Fisetin; SCC-4 cells; apoptosis; mitochondria

PMID:
28181380
DOI:
10.1002/tox.22396
[Indexed for MEDLINE]

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