[논문]A Bacterial Metabolite, Compound K, Induces Programmed Necrosis in MCF-7 Cells via GSK3β

Kwak, Chae Won; Son, Young Min; Gu, Min Jeong; Kim, Girak; Lee, In Kyu; Kye, Yoon Chul; Kim, Han Wool; Song, Ki-Duk; Chu, Hyuk; Park, Byung-Chul; Lee, Hak-Kyo; Yang, Deok-Chun; Sprent, Jonathan; Yun, Cheol-Heui

doi:10.4014/jmb.1505.05057

[국내논문] A Bacterial Metabolite, Compound K, Induces Programmed Necrosis in MCF-7 Cells via GSK3β 원문보기

Journal of microbiology and biotechnology, v.25 no.7, 2015년, pp.1170 - 1176

Abstract ▼ AI-Helper

Ginsenosides, the major active component of ginseng, are traditionally used to treat various diseases, including cancer, inflammation, and obesity. Among these, compound K (CK), an intestinal bacterial metabolite of the ginsenosides Rb1, Rb2, and Rc from Bacteroides JY-6, is reported to inhibit cancer cell growth by inducing cell-cycle arrest or cell death, including apoptosis and necrosis. However, the precise effect of CK on breast cancer cells remains unclear. MCF-7 cells were treated with CK ($0-70{\mu}M$) for 24 or 48 h. Cell proliferation and death were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Changes in downstream signaling molecules involved in cell death, including glycogen synthase kinase $3\beta$ ($GSK3\beta$), $GSK3\beta$, $\beta$-catenin, and cyclin D1, were analyzed by western blot assay. To block $GSK3\beta$ signaling, MCF-7 cells were pretreated with $GSK3\beta$ inhibitors 1 h prior to CK treatment. Cell death and the expression of $\beta$-catenin and cyclin D1 were then examined. CK dose- and time-dependently inhibited MCF-7 cell proliferation. Interestingly, CK induced programmed necrosis, but not apoptosis, via the $GSK3\beta$ signaling pathway in MCF-7 cells. CK inhibited $GSK3\beta$ phosphorylation, thereby suppressing the expression of $\beta$-catenin and cyclin D1. Our results suggest that CK induces programmed necrosis in MCF-7 breast cancer cells via the $GSK3\beta$ signaling pathway.

주제어

AI 본문요약
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제안 방법

However, its mechanism of action remains unclear. The aim of the study was to evaluate the anticancer effects of CK in the human breast cancer cell line MCF-7, focusing particularly on programmed necrosis and its associated signaling pathways. We investigated whether CK (i) has anticancer activity in MCF-7 cells and (ii) induces cell death via GSK3β.

성능/효과

Moreover, GSK3β is involved in regulating various functions, including cell survival and death [15]. In our study, CK treatment induced GSK3β dephosphorylation, and reduced the expression of β-catenin and cyclin D1, suggesting that CK is associated with GSK3β-mediated programmed necrosis.
Nevertheless, our study revealed that CK did not suppress MCF-7 cell proliferation via these pathways. It is important to note that the previous report suggesting apoptotic MCF-7 cell death following CK treatment used DNA fragmentation and cell viability assays, which are limited in defining the type of cell death.
It has also been reported that PARP-1-dependent programmed necrosis relies on AIF [2]. Our results indicated that CK induces high AIF expression levels (data not shown), suggesting that CK induces programmed necrosis.
We investigated whether CK (i) has anticancer activity in MCF-7 cells and (ii) induces cell death via GSK3β. Our results showed that CK dose- and time-dependently inhibited MCF-7 cell proliferation and reduced GSK3β phosphorylation.
To examine whether CKinduced cell death was mediated via GSK3β, the cells were pretreated with GSK3β inhibitor VIII (GSK3βi) followed by CK treatment, and necrosis was examined by using flow cytometry. The results showed that necrosis in the cells pretreated with GSK3βi and then treated with CK were decreased when compared with the cells treated with CK alone (Fig. 3B).

후속연구

Understanding the involvement and the precise role of GSK3β signaling could become important for the development of therapeutic strategies to improve the efficacy of anticancer agents. Therefore, the present study provides a potential target for future investigation in breast cancer therapy.

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