Inhibitory effects of eupatilin on tumor invasion of human gastric cancer MKN-1 cells
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RESEARCH ARTICLE
Inhibitory effects of eupatilin on tumor invasion of human gastric cancer MKN-1 cells Byeong Bae Park & Jin sun Yoon & Eun shil Kim & Jiyoung Choi & Young woong Won & Jung hye Choi & Young Yiul Lee
Received: 21 August 2012 / Accepted: 6 December 2012 / Published online: 8 January 2013 # International Society of Oncology and BioMarkers (ISOBM) 2013
Abstract Extracts of the whole herb of Artemisia asiatica Nakai (Asteraceae) are used in traditional oriental medicine to treat inflammation. Eupatilin (5,7-dihydroxy-3′,4′,6-trimethoxyflavone) is one of the pharmacologically active components found in A. asiatica, and has been shown to possess anti-tumoral effects in some malignancies, including gastric cancer. However, its anti-metastatic effect in gastric cancer is hardly known. In this study, antimetastatic effect of eupatilin was investigated in the human gastric cancer cell line, MKN-1. Eupatilin inhibited MKN-1 growth in a dose- and a time-dependent manner, and induced apoptosis with a concomitant increase of caspase-3 activity. ELISA demonstrated that release of proinflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-8) was significantly reduced by eupatilin. And p-AKT and pERK (p44/42) was reduced. Expression level of β-catenin and integrin was reduced and p-GSKβ was increased. In transcription reporter system, the activity of the transcriptional factor, NF-κB, was reduced by eupatilin and the expression of p65 was down-regulated when MKN-1 cells were treated with eupatilin. Moreover, a zymography study revealed that this reduction in invasive potential resulted from a reduction in type IV collagenolytic (gelatinolytic) activity. The expressions of metalloproteinases (MMP-2 and MMP-9) were also reduced in MKN-1 cells treated with B. B. Park : J. s. Yoon : E. s. Kim : J. Choi : Y. w. Won : J. h. Choi : Y. Y. Lee Department of Internal Medicine, Han Yang University College of Medicine, Seoul, South Korea Y. Y. Lee (*) Division of Hematology/Oncology, Department of Internal Medicine, Han Yang University Hospital, 17 Haeng Dang-dong, Sung Dong-ku, Seoul 133-792, South Korea e-mail: [email protected]
eupatilin. In vitro invasion assay, eupatilin inhibited MKN-1 penetrating reconstituted basement membrane barriers. These results suggest that eupatilin inhibits the MKN-1 gastric cancer cell proliferation via activation of caspase-3 and the metastatic potential of gastric cancer cells via downregulation of NF-κB activity followed by reduction of proinflammatory cytokine-mediated MMPs expressions. Keywords Growth inhibition . Gastric cancer . Eupatilin . Metastasis . Invasion
Introduction Two characteristic features define a cancer. Unregulated cell growth and tissue invasion/metastasis. Metastasis is significantly influenced by changes of gene expression and microenvironmental factors. To complete metastasis, tumor cells invade surrounding tissues and vascular or lymphatic vessels form metastatic colonies at distant sites after degrading components of the extracellular matrix (ECM). Cells change their
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