Induction of Apoptosis by Citrus unshiu Peel in Human Breast Cancer MCF-7 Cells: Involvement of ROS-Dependent Activation of AMPK
- Authors
- Kim, Min Yeong; Bo, Hyun Hwang; Choi, Eun Ok; Kwon, Da He; Kim, Hong Jae; Ahn, Kyu Im; Ji, Seon Yeong; Jeong, Jin-Woo; Park, Shin-Hyung; Hong, Su-Hyun; Kim, Gi-Young; Park, Cheol; Kim, Heui-Soo; Moon, Sung-Kwon; Yun, Seok-Joong; Kim, Wun Jae; Choi, Yung Hyun
- Issue Date
- May-2018
- Publisher
- PHARMACEUTICAL SOC JAPAN
- Keywords
- Citrus unshiu peel; breast cancer cell; apoptosis; AMP-activated protein kinase; reactive oxygen species
- Citation
- BIOLOGICAL & PHARMACEUTICAL BULLETIN, v.41, no.5, pp 713 - 721
- Pages
- 9
- Journal Title
- BIOLOGICAL & PHARMACEUTICAL BULLETIN
- Volume
- 41
- Number
- 5
- Start Page
- 713
- End Page
- 721
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/968
- DOI
- 10.1248/bpb.b17-00898
- ISSN
- 0918-6158
1347-5215
- Abstract
- The fruit of Citrus unshiu MARKOVICH used for various purposes in traditional medicine has various pharmacological properties including antioxidant, anti-inflammatory, and antibacterial effects. Recently, the possibility of anti-cancer activity of the extracts or components of this fruit has been reported; however, the exact mechanism has not yet been fully understood. In this study, we evaluated the anti-proliferative effect of water extract of C. unshiu peel (WECU) on human breast cancer MCF-7 cells and investigated the underlying mechanism. Our results showed that reduction of MCF-7 cell survival by WECU was associated with the induction of apoptosis. WECU-induced apoptotic cell death was related to the activation of caspase-8 and -9, representative initiate caspases of extrinsic and intrinsic apoptosis pathways, respectively, and increase in the Bax :Bc1-2 ratio accompanied by cleavage of poly(ADP-ribose) polymerase (PARP). WECU also increased the mitochondrial dysfunction and cytosolic release of cytochrome c. In addition, AMP -activated protein kinase (AMPK) and its downstream target molecule, acetyl-CoA carboxylase, were activated in a concentration dependent manner in WECU-treated cells. In contrast, compound C, an AMPK inhibitor, significantly inhibited WECU-induced apoptosis, while inhibiting increased expression of Bax and decreased expression of Bcl-2 by WECU and inhibition of WECU-induced PARP degradation. Furthermore, WECU provoked the production of reactive oxygen species (ROS); however, the activation of AMKP and apoptosis by WECU were prevented, when the ROS production was blocked by antioxidant N-acetyl cysteine. Therefore, our data indicate that WECU suppresses MCF-7 cell proliferation by activating the intrinsic and extrinsic apoptosis pathways through ROS-dependent AMPK pathway activation.
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