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The Journal of Internal Korean Medicine > Volume 37(1); 2016 > Article
The Journal of Internal Korean Medicine 2016;37(1): 65-76.
5637 인체 방광암세포의 이동성과 침윤성에 미치는 황흑산(黃黑散)의 영향
심원석1, 김민서1, 박상은1, 최영현2, 홍상훈1
1동의대학교 한의과대학 한방내과
2동의대학교 한의과대학 생화학교실
Inhibition of Migration and Invasion of Human Bladder Cancer 5637 cells by Hwangheuk-san
Won-suk Shim1, Min-serh Kim1, Sang-eun Park1, Yung-hyun Choi2, Sang-hoon Hong1
1Dept. of Korean Internal Medicine, College of Korean Medicine, Dong-Eui University
2Dept. of Biochemistry, College of Korean Medicine, Dong-Eui University
Correspondence  Sang-hoon Hong ,Tel: 051-850-8810, Fax: 051-867-5162, Email: shhong@deu.ac.kr
Received: February 16, 2016,   Accepted: March 25, 2016,   Published online: March 31, 2016.
ABSTRACT
Objectives:
The purpose of this study was to identify the inhibitory effects of Hwangheuk-san (HHS), a Korean multi-herb formula comprising four medicinal herbs, on cell migration and invasion, two critical cellular processes that are often deregulated during metastasis, using the human bladder cancer 5637 cell line.

Methods:
Cell viability, motility, and invasion were assessed by 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphnyl-2H-tetrazolium bromide (MTT), wound healing migration, and Transwell assays, respectively. Gene expression was detected by Western blot analysis. In addition, the activities of matrix metalloproteinases (MMPs) and the values for transepithelial electrical resistance (TER) were analyzed using a Gelatinase Activity Assay Kit and an Epithelial Tissue Voltohmmeter, respectively.

Results:
Our data indicated that within the concentration range that was not cytotoxic, HHS effectively inhibited the cell motility and invasiveness of 5637 cells. HHS markedly decreased the expression and activity of MMP-2 and MMP-9, which was associated with unregulation of tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2. Further investigation revealed that phosphorylation of phosphatidylinositol 3-kinase (PI3K) and AKT was decreased in HHS-treated 5637 cells, and a PI3K/AKT inhibitor synergistically reduced the inhibition of migration and invasion and also inactivated MMP-2 and MMP-9. Moreover, HHS increased the tightening of tight junctions (TJs), which was demonstrated by an increase in the TER, and reduced the expression the levels of claudin family members (claudin-3 and -4), which are major components involved in the tightening of TJs.

Conclusions:
The present findings demonstrated that HHS attenuated the migration and invasion of bladder cancer 5637 cells by modulating the activity of the PI3K/Akt signaling pathway and also through TJ tightening.
Key words: Hwangheuk-san, invasion, MMP, PI3K/Akt, tight junction
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