Involvement of Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and the PI3KAKTmTOR Pathway in Nobiletin-Induced Apoptosis of Human Bladder Cancer Cells

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Title:	Involvement of Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and the PI3KAKTmTOR Pathway in Nobiletin-Induced Apoptosis of Human Bladder Cancer Cells
Authors:	Goan, Yih-Gang Wu, Wen-Tung Liu, Chih-I Neoh, Choo-Aun Wu, Yu-Jen
Contributors:	健康暨護理學院
Keywords:	nobiletin mitochondrial dysfunction endoplasmic reticulum stress PI3K/AKT/ mTOR pathway
Date:	2019
Issue Date:	2020-09-24T05:51:18Z (UTC)
Abstract:	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 M inhibited cell growth by 42%, 62%, and 80%, respectively. Cells treated with 60 M 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/elF2/ATF4/CHOP pathway, and downregulating the PI3K/AKT/mTOR pathway. Our results suggested that the cytotoxic and apoptotic eects of NOB on bladder cancer cells are associated with endoplasmic reticulum stress and mitochondrial dysfunction.
Appears in Collections:	[Department of Food Science and Nutrition] Papers

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