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KMID : 0613820190290040410
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Journal of Life Science
2019 Volume.29 No. 4 p.410 ~ p.420
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Relationship between Reactive Oxygen Species and Adenosine Monophosphate-activated Protein Kinase Signaling in Apoptosis Induction of Human Breast Adenocarcinoma MDA-MB-231 Cells by Ethanol Extract of Citrus unshiu Peel
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Kim Min-Yeong
Hwangbo Hyun
Ji Eun-Sun
Hong Su-Hyun
Choi Sung-Hyun
Kim Sung-Ok
Park Cheol
Choi Yung-Hyun
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Abstract
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Citrus unshiu peel extracts possess a variety of beneficial effects, and studies on their anticancer activity have been reported. However, the exact mechanisms underlying this activity remain unclear. In the current study, the apoptotic effect of ethanol extract of C. unshiu peel (EECU) on human breast adenocarcinoma MDA-MB-231 cells and related mechanisms were investigated. The results showed that the survival rate of MDA-MB-231 cells treated with EECU was significantly inhibited in a concentration- dependent manner, which was associated with the induction of apoptosis. EECU-induced apoptosis was associated with the activation of caspase-8 and caspase-9, which initiate extrinsic and intrinsic apoptosis pathways, respectively, and caspase-3, a representative effect caspase. EECU suppressed the expression of the inhibitor of apoptosis family of proteins, leading to an increased Bax/Bcl-2 ratio and proteolytic degradation of poly (ADP-ribose) polymerase. EECU also enhanced the loss of the mitochondrial membrane potential and cytochrome c release from the mitochondria to the cytosol, along with truncation of Bid. In addition, EECU activated AMP-activated protein kinase (AMPK), and compound C, an AMPK inhibitor, significantly weakened EECU-induced apoptosis and cell viability reduction. Furthermore, EECU promoted the generation of reactive oxygen species (ROS), which acted as upstream signals for AMPK activation as pretreatment of cells, with the antioxidant N-acetyl cysteine reversing both EECU-induced AMPK activation and apoptosis. Collectively, these findings suggest that EECU inhibits MDA-MB-231 adenocarcinoma cell proliferation by activating intrinsic and extrinsic apoptotic pathways, which was mediated through ROS/AMPK-dependent pathways.
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KEYWORD
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AMPK, apoptosis, breast cancer cells, Citrus unshiu peel, ROS
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