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Open AccessArticle

Involvement of Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and the PI3K/AKT/mTOR Pathway in Nobiletin-Induced Apoptosis of Human Bladder Cancer Cells

by 1,2,3, 4, 3, 5,*,† and 3,6,7,*,†
1
Department of Surgery, Kaohsiung Veterans General Hospital Pingtung Branch, Pingtung 91202, Taiwan
2
Division of Thoracic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
3
Department of Nursing, Meiho University, Pingtung 91202, Taiwan
4
Department of Food Science and Nutrition, Meiho University, Pingtung 91202, Taiwan
5
Department of Research, Pingtung Christian Hospital, Pingtung 90059, Taiwan
6
Department of Biological Technology, Meiho University, Pingtung 91202, Taiwan
7
Yu Jun Biotechnology Co., Ltd., Kaohsiung 81363, Taiwan
*
Authors to whom correspondence should be addressed.
The authors contributed equally to this work.
Academic Editors: Jianbo Xiao, Yanbo Zhang and Hui Ni
Molecules 2019, 24(16), 2881; https://doi.org/10.3390/molecules24162881
Received: 15 July 2019 / Revised: 1 August 2019 / Accepted: 6 August 2019 / Published: 8 August 2019
(This article belongs to the Special Issue Phytochemicals in Medicine and Food)
Nobiletin (NOB) is a polymethoxylated flavonoid isolated from citrus fruit peel that has been shown to possess anti-tumor, antithrombotic, antifungal, anti-inflammatory and anti-atherosclerotic activities. The main purpose of this study was to explore the potential of using NOB to induce apoptosis in human bladder cancer cells and study the underlying mechanism. Using an MTT assay, agarose gel electrophoresis, a wound-healing assay, flow cytometry, and western blot analysis, this study investigated the signaling pathways involved in NOB-induced apoptosis in BFTC human bladder cancer cells. Our results showed that NOB at concentrations of 60, 80, and 100 μM inhibited cell growth by 42%, 62%, and 80%, respectively. Cells treated with 60 μM NOB demonstrated increased DNA fragmentation, and flow cytometry analysis confirmed that the treatment caused late apoptotic cell death. Western blot analysis showed that mitochondrial dysfunction occurred in NOB-treated BFTC cells, leading to cytochrome C release into cytosol, activation of pro-apoptotic proteins (caspase-3, caspase-9, Bad, and Bax), and inhibition of anti-apoptotic proteins (Mcl-1, Bcl-xl, and Bcl-2). NOB-induced apoptosis was also mediated by regulating endoplasmic reticulum stress via the PERK/elF2α/ATF4/CHOP pathway, and downregulating the PI3K/AKT/mTOR pathway. Our results suggested that the cytotoxic and apoptotic effects of NOB on bladder cancer cells are associated with endoplasmic reticulum stress and mitochondrial dysfunction. View Full-Text
Keywords: nobiletin; mitochondrial dysfunction; endoplasmic reticulum stress; PI3K/AKT/mTOR pathway nobiletin; mitochondrial dysfunction; endoplasmic reticulum stress; PI3K/AKT/mTOR pathway
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Goan, Y.-G.; Wu, W.-T.; Liu, C.-I.; Neoh, C.-A.; Wu, Y.-J. Involvement of Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and the PI3K/AKT/mTOR Pathway in Nobiletin-Induced Apoptosis of Human Bladder Cancer Cells. Molecules 2019, 24, 2881.

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