Biochemical and Biophysical Research Communications
Chikusetsusaponin IVa methyl ester induces cell cycle arrest by the inhibition of nuclear translocation of β-catenin in HCT116 cells
Graphical abstract
Introduction
Colorectal cancer is caused by multiple transition steps, including the accumulation of genetic errors [1], [2]. Previous studies discovered several critical genes and pathways that regulate the progression of colorectal cancers [3]. Among those mutated genes, genetic mutations in the Wnt/β-catenin signaling pathway increase the progression of colorectal cancer through the up-regulation of β-catenin transcriptional activity [4], [5], [6]. The Wnt/β-catenin signaling pathway affects cellular developmental processes and human carcinogenesis through the activation of genes associated with cell proliferation, such as c-jun, c-myc, fibronectin, cyclinD1 and fra-1 [7], [8], [9], [10], [11]. Thus, inhibition of the Wnt/β-catenin signaling pathway can be an important candidate for drug targeting for the treatment of colorectal cancers.
Inhibition of the Wnt/β-catenin signaling pathway may be a useful treatment for colorectal cancer through the induction of cell cycle arrest. Some compounds from natural products inhibit the Wnt/β-catenin signaling pathway. For example, quercetin, fisetin, curcumin, resveratrol and genistein are well-known inhibitors of the pathway. Moreover, lignans, which are cancer chemopreventive agents, have also been reported to inhibit the Wnt/β-catenin signaling pathway [12], [13], [14], [15], [16]. These previous studies imply that natural compounds, including dietary compounds, are potential inhibitors of the Wnt/β-catenin signaling pathway and may inhibit colon cancer proliferation. Among natural compounds, saponins are well known to have an anticancer activity [17], [18], [19]. However, it is not well known that saponins may serve as an inhibitor for Wnt/β-catenin signaling.
In this study, we investigated whether chikusetsusaponin IVa methyl ester (CME), a triterpenoid saponin from the root of Achyranthes japonica, disrupts Wnt/β-catenin signaling to inhibit cell proliferation in colon cancer cells. We elucidated the underlying mechanism of the regulation by treating cells with CME. We used a molecular assay to observe the cell cycle distribution and apoptosis and measured the ability of β-catenin binding, its transcriptional activity and changes in protein expression in HCT116 cells treated with CME.
Section snippets
Plant material, extraction and isolation
The root of A. japonica was purchased and identified by Professor Jehyun Lee (College of Oriental Medicine, Dongguk University, Gyeongju, Korea). The dried root of A. japonica (12.15 kg) was extracted with methanol (60 ℓ) under reflux 3 times, and the filtrate was concentrated under reduced pressure to give the methanol extract (962.16 g). The methanol extract was suspended in H2O and partitioned with hexane (20 ℓ), ethylacetate (20 ℓ) and butanol (20 ℓ) to yield hexane (45.04 g), ethylacetate
CME inhibits cell proliferation in HCT116 cells
To investigate the anticancer activity of CME (the chemical structure shown in Fig. 1A) in colorectal cancer cells, we used HCT116 cells, which are colon cancer cells with mutations in the β-catenin gene [6]. First, we performed the cell viability assay that measures cellular mitochondrial dehydrogenase activity. We treated the cells with different concentrations of CME, as shown in Fig. 1B. CME decreased the cell proliferation of HCT116 cells in the range of 25 μM and 50 μM and caused severe
Discussion
Here, we report the anticancer activity of chikusetsusaponin IVa methyl ester (CME) and elucidate its molecular mechanism. CME induced cell cycle arrest by inhibiting β-catenin nuclear translocation in HCT116 cells. The Wnt/β-catenin signaling pathway is significant in human cancer because mutations of the pathway's components, such as Axin, APC and β-catenin, are common causes of cancer progression [24]. Mutations in the APC gene as a negative regulator of Wnt/β-catenin signaling are typically
Conflict of interest
None.
Acknowledgments
This work was supported by grants from the National Research Foundation of Korea (MRC 2009-93146) and KIST intramural research (2z04381).
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