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Gilgyung-tang Inhibits the Migration and Invasion of Human Bladder Cancer 5637 Cells through the Tightening of Tight Junctions and Inhibition of Matrix Metalloproteinase Activity  

Hong, Su-hyun (Dept. of Biochemistry, College of Korean Medicine, Dong-Eui University)
Choi, Yung-hyun (Dept. of Biochemistry, College of Korean Medicine, Dong-Eui University)
Publication Information
The Journal of Internal Korean Medicine / v.37, no.1, 2016 , pp. 16-25 More about this Journal
Abstract
Objectives: Gilgyung-tang (GGT) has been used as one of the main multi-herb formulas to treat “Peo-ong” (lung abscess). In this study, we investigated the inhibitory effects of water extracts of GGT on cell migration and invasion, two critical cellular processes that are often deregulated during metastasis, in human bladder cancer 5637 cells.Methods: Effects on cell viability were quantified using an MTT assay. To analyze the anti-metastatic effects, we conducted a wound healing migration assay, an in vitro invasiveness assay, and a measurement of the transepithelial electrical resistance (TER). The expression of protein and mRNA were measured by Western blotting and real-time polymerase chain reaction (RT-PCR), respectively.Results: GGT markedly inhibited the cell motility and invasiveness of 5637 cells within the concentration range that was not cytotoxic. The inhibitory effects of GGT on cell invasiveness were associated with tightening of the tight junctions (TJs), which was demonstrated by an increase in the TER. The RT-PCR and Western blotting results indicated that GGT decreased the levels of claudin proteins. GGT also inhibited the activity and expression of matrix metalloproteinase (MMP)-2 and -9 and simultaneously increased the levels of tissue inhibitor of metalloproteinase-1 and -2.Conclusions: Our findings suggest that GGT reduces both the migration and the invasion of 5637 cells by modulating the activity of TJs and MMPs.
Keywords
Gilgyung-tang; invasion; tight junctions; claudin; matrix metalloproteinase;
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1 Vihinen P, Ala-aho R, Kähäri VM. Matrix metalloproteinases as therapeutic targets in cancer. Curr Cancer Drug Targets 2005;5(3):203-20.   DOI
2 John A, Tuszynski G. The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res 2001;7(1):14-23.   DOI
3 Gibbs DF, Warner RL, Weiss SJ, Johnson KJ, Varani J. Characterization of matrix metalloproteinases produced by rat alveolar macrophages. Am J Respir Cell Mol Biol 1999;20(6):1136-44.   DOI
4 Mook OR, Frederiks WM, Van Noorden CJ. The role of gelatinases in colorectal cancer progression and metastasis. Biochim Biophys Acta 2004;1705(2):69-89.
5 Lombard C, Saulnier J, Wallach J. Assays of matrix metalloproteinases (MMPs) activities: a review. Biochimie 2005;87(3-4):265-72.   DOI
6 Lambert E, Dasse E, Haye B, Petitfrere E. TIMPs as multifacial proteins. Crit Rev Oncol Hematol 2004;49(3):187-98.   DOI
7 Brown GT, Murray G. Current mechanistic insights into the roles of matrix metalloproteinases in tumour invasion and metastasis. J Pathol 2015;237(3):273-81.   DOI
8 Schneeberger EE, Lynch RD. The tight junction: a multifunctional complex. Am J Physiol Cell Physiol 2004;286(6):1213-28.   DOI
9 Soler AP, Miller RD, Laughlin KV, Carp NZ, Klurfeld DM, Mullin JM. Increased tight junctional permeability is associated with the development of colon cancer. Carcinogenesis 1999;20(8):1425-31.   DOI
10 Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, et al. Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene 2003;22(13):2021-33.   DOI
11 Tagliarino C, Pink JJ, Dubyak GR, Nieminen AL, Boothman DA. Calcium is a key signaling molecule in beta-lapachone-mediated cell death. J Biol Chem 2001;276(22):19150-9.   DOI
12 Székely E, Törzsök P, Riesz P, Korompay A, Fintha A, Székely T, et al. Expression of claudins and their prognostic significance in noninvasive urothelial neoplasms of the human urinary bladder. J Histochem Cytochem 2011;59(10):932-41.   DOI
13 Törzsök P, Riesz P, Kenessey I, Székely E, Somorácz A, Nyirády P, et al. Claudins andki-67: potential markers to differentiate low-and high-grade transitional cell carcinomas of the urinary bladder. J Histochem Cytochem 2011;59(11):1022-30.   DOI
14 Hewitt KJ, Agarwal R, Morin PJ. The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer 2006;6:186.   DOI
15 Mauro L, Bartucci M, Morelli C, Andò S, Surmacz E. IGF-I receptor-induced cell-cell adhesion of MCF-7 breast cancer cells requires the expression of junction protein ZO-1. J Biol Chem 2001; 276(43):39892-7.   DOI
16 Du J, Tang XL. Natural products against cancer: a comprehensive bib liometric study of the research projects, publications, patents and drugs. J Cancer Res Ther 2014;10(Suppl 1):27-37.   DOI
17 李珩九. 桔梗湯이 이 人體 肺細胞에 미치는 影響에 關한 分子生物學的 硏究, 대한한의학회지 1999;20(2):88-97.
18 虞搏. 醫學正傳. 서울: 성보사; 1986, p. 307-8.
19 黃度淵. 對譯 證脈·方藥合編. 서울: 남산당;1992, p. 259-60.
20 許浚. 東醫寶鑑. 서울: 법인문화사; 1999, p. 1433.
21 차은수, 조일현, 이경기, 조영민, 정희재, 정승기,등. 폐색성(閉塞性) 폐염(肺炎)을 겸(蒹)한 폐암환자(肺癌患者)의 한방(韓方) 치료(治療) 1례(例). 대한암한의학회지 1997;3(1):207-19.
22 전종철, 강필구, 박동일, 최원철. 수종의 한약처방이 폐암세포에 미치는 영향. 대한한방내과학회지 2000;21(4):621-31.
23 이주희, 정희재, 정승기, 이형구. 桔梗湯과 桔梗湯加味方이 S-180에 대한 抗癌效果 및 免疫反應에 關한 實驗的 硏究. 경희한의대논문집 1998;21(1):225-50.
24 고영철, 이승언, 박병민, 노승석, 조남근, 이시형,등. 肺癌細胞에서 桔梗湯의 抗癌機轉硏究. 대한한의정보학회지 2003;9(2):94-113.
25 Singh AB, Sharma A, Dhawan P. Claudin family of proteins and cancer: an overview. J Oncol 2010;2010:541957.
26 Turksen K, Troy TC. Junctions gone bad: claudins and loss of the barrier in cancer. Biochim Biophys Acta 2011;1816(1):73-9.
27 Angelow S, Yu AS. Claudins and paracellular transport: an update. Curr Opin Nephrol Hypertens 2007;16(5):459-64.   DOI
28 Morin PJ. Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res 2005;65(21):9603-6.   DOI
29 Agarwal R, D'Souza T, Morin PJ. Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. Cancer Res 2005;65(16):7378-85.   DOI
30 Yoon CH, Kim MJ, Park MJ, Park IC, Hwang SG, An S, et al. Claudin-1 acts through c-Abl-proteinkinase Cdelta (PKCd) signaling and has a causal role in the acquisition of invasive capacity in human liver cells. J Biol Chem 2010;285(1):226-33.   DOI
31 Grant-Tschudy KS, Wira CR. Effect of oestradiol on mouse uterine epithelial cell tumour necrosis factor-alpha release is mediated through uterine stromal cells. Immunology 2005;115(1):99-107.   DOI