Anti-invasive Activity of Ethanol Extracts of Ganoderma lucidum through Tightening of Tight Junctions and Inhibition of Matrix Metalloproteinase Activities in Human Gastric Carcinoma Cells

다국어 초록 (Multilingual Abstract)

This study investigated the effect of ethanol extracts of Ganoderma lucidum (EGL) on the correlation between tightening of the tight junctions (TJs) and the anti-invasive activity in human gastric adenocarcinoma AGS cells to elucidate further the possible anticancer mechanisms that G lucidum exerts. Within the concentrations of EGL that were not cytotoxic,EGL markedly inhibited the cell motility and invasiveness in a concentrationdependent manner. The activities of matrix metalloproteinases (MMP)-2 and MMP-9 in AGS cells were dose-dependently inhibited by treatment with EGL, and this was correlated with a decrease in expression of their mRNA and proteins and the upregulation of the expression of the tissue inhibitors of metalloproteinases. The anti-invasive activity of EGL was also found to be associated with the increased tightness of the TJ, which was demonstrated by an increase in transepithelial electrical resistance. Additionally,EGL repressed the levels of the claudin family members, which are major components of TJs that play a key role in the control and selectivity of paracellular transport. Furthermore,the levels of E-cadherin, a type I transmembrane glycoprotein, were inhibited by EGL treatment, however, those of snail, an epithelial to mesenchymal transition regulator and zinc finger transcription factor, were concentration-dependently increased in response to EGL treatment. Although further studies are needed, the present study indicates that TJs and MMPs are crucial targets of EGL-induced anti-invasiveness in human gastric cancer AGS cells.

참고문헌 (Reference)

1 Mahajna J, "Wasser SP.Pharmacological values of medicinal mushrooms for prostatecancertherapy: thecase of Ganoderma lucidum" 61 : 6-26, 2009

2 Latorre IJ, "Viral oncoprotein-induced mislocalization of select PDZproteins disrupts tight junctions and causes polarity defects inepithelial cells" 118 : 4283-4293, 2005

3 Lin SB, "Triterpene-enriched extractsfrom Ganoderma lucidum inhibit growth of hepatoma cells viasuppressing protein kinase C, activating mitogen-activatedprotein kinases and G2-phase cell cycle arrest" 72 : 2381-2390, 2003

4 Rangel LB, "Tight junction proteins claudin-3 andclaudin-4 are frequently overexpressed in ovarian cancer butnot in ovarian cystadenomas" 9 : 2567-2575, 2003

5 Schneeberger EE, "The tight junction: a multifunctional complex" 286 : 1213-1228, 2004

6 Mook OR, "The role of gelatinases in colorectal cancer progression and metastasis" 1705 : 69-89, 2004

7 Jiang WG, "The molecular and cellularbasis ofcancerinvasionand metastasis and itsimplicationsfortreatment" 81 : 1576-1590, 1994

8 Matrisian LM, "The matrix-degrading metalloproteinases" 14 : 455-463, 1992

9 Lambert E, "TIMPs as multifacialproteins" 49 : 187-198, 2004

10 Usami Y, "Snail-associated epithelial-mesenchymaltransition promotes oesophageal squamous cell carcinomamotility and progression" 215 : 330-339, 2008

11 Yokoyama K, "Reverse correlation of E-cadherin and snailexpression in oral squamous cell carcinoma cells in vitro" 37 : 65-71, 2001

12 Verghese GM, "Prostasin regulatesepithelial monolayer function: cell-specific Gpld1-mediatedsecretion and functional role for GPI anchor" 291 : 1258-1270, 2006

13 Chien CM, "Polysaccharides of Ganoderma lucidum alter cellimmunophenotypic expression and enhance CD56þNK-cellcytotoxicity in cord blood" 12 : 5603-5609, 2004

14 McLachlan RW, "Not so simple: the complexity of phosphotyrosine signaling at cadherin adhesive contacts" 85 : 545-554, 2007

15 Hart IR, "Molecular aspects of the metastaticcascade" 989 : 65-84, 1989

16 Duffy MI, "Metalloproteinases:role in breast carcinogenesis, invasion andmetastasis" 2 : 252-257, 2000

17 Vihinen P, "Matrix metalloproteinases astherapeutic targetsincancer" 5 : 203-220, 2005

18 MartinTA, "Loss of tight junction barrier function and its role in cancer meta stasis" 1788 : 872-891, 2009

19 Kominsky SL, "Loss of the tight junction protein Claudin-7 correlateswith histological grade in both ductal carcinoma in situ andinvasive ductal carcinoma of the breast" 22 : 2021-2033, 2003

20 Mullin JM, "Keynotereview: epithelial and endothelial barriers in human disease" 10 : 395-408, 2005

21 Ip YC, "Inhibition of hepatocellularcarcinoma invasion by suppression of Claudin-10 inHLE cells" 6 : 858-2867, 2007

22 Shin DY, "Induction of apoptosis and inhibition of invasion in human hepatoma cells by anthocyanins from meoru" 1171 : 137-148, 2009

23 KimSO, "Induction of Egr-1 is associated with anti-metastatic and anti-invasive ability of b-lapachone in human hepatocarcinoma cells" 71 : 2169-2176, 2007

24 Kyung-Jun Jang, "Induction of Apoptosis by Ethanol Extracts of Ganoderma lucidum in Human Gastric Carcinoma Cells" 세계약침학회 3 (3): 24-31, 2010

25 Soler AP, "Increased tight junction alperme ability is associated with the development of colon cancer" 20 : 1425-1431, 1999

26 UzuiH, "Increased expression of membrane type 3-matrix metallo protein ase in human atherosclerotic plaque: role of activated macrophagesandinflammatorycytokines" 106 : 3024-3030, 2002

27 ChenJG, "Gene expression and mitotic exit induced by microtubule-stabilizing drugs" 63 : 7891-7899, 2003

28 Stanley G, "Ganodermalucidum suppresses angiogenesis through the inhibition ofsecretion of VEGF and TGF-b1 from prostate cancer cells" 330 : 46-52, 2005

29 Sliva D, "Ganoderma lucidum suppresses motility of highly invasivebreast and prostate cancer cells" 298 : 603-612, 2002

30 Jiang JH, "Ganoderma lucidum inhibits proliferation and inducesapoptosis in human prostate cancer cells PC-3" 24 : 1093-1099, 2004

31 Hu H, "Ganoderma lucidum extract induces cell cycle arrest and apoptosis in MCF-7 human breast cancer cell" 102 : 250-253, 2002

32 Mu¨ller CI, "Ganoderma lucidum causes apoptosis in leukemia,lymphoma and multiple myeloma cells" 30 : 841-848, 2006

33 Boh B, "Ganoderma lucidum andits pharmaceutically active compounds" 13 : 265-301, 2007

34 Paterson RR, "Ganoderma - a therapeutic fungal biofactory" 67 : 1985-2001, 2006

35 Hong KJ, "Effects of Ganodermalucidum on apoptotic and anti-inflammatory function in HT-29human colonic carcinoma cells" 18 : 768-770, 2004

36 Young-Rae Lee, "Cordycepin inhibits UVB-induced matrix metalloproteinase expression by suppressing the NF-κB pathway in human dermal fibroblasts" 생화학분자생물학회 41 (41): 548-554, 2009

37 Nelson WJ, "Convergence of Wnt, b-catenin, andcadherin pathways" 303 : 1483-1487, 2004

38 Kominsky SL, "Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated throughtight junction proteins Claudin3 and 4" 164 : 1627-1633, 2004

39 Kominsky SL, "Claudins: emerging targets for cancer therapy" 8 : 1-11, 2006

40 Van Itallie CM, "Claudins and epithelial paracellulartransport" 68 : 403-429, 2006

41 Cunningham SC, "Claudin-4, mitogen activatedprotein kinase kinase 4, and stratifin are markers of gastricadenocarcinoma precursor lesions" 15 : 281-287, 2004

42 MichlP, "Claudin-4 expression decreases invasiveness and metastaticpotential of pancreatic cancer" 63 : 6265-6271, 2003

43 Agarwal R, "Claudin-3 and claudin-4expression in ovarian epithelial cells enhances invasion and isassociated with increased matrix metalloproteinase-2 activity" 65 : 7378-7385, 2005

44 Toke´s AM, "Claudin-1, -3 and -4 proteins and mRNA expression in benignand malignant breast lesions: a research study" 7 : 296-305, 2005

45 Yoon CH, "Claudin-1 acts through c-Abl-protein kinase Cdelta (PKCd)signaling and has a causal role in the acquisition of invasivecapacity in human liver cells" 285 : 226-233, 2010

46 Morin PJ, "Claudin proteins in human cancer: promising newtargets for diagnosis and therapy" 65 : 9603-9606, 2005

47 Miyamori H, "Claudin promotes activation of pro-matrix metalloproteinase-2mediated by membrane-type matrix metalloproteinases" 276 : 28204-28211, 2001

48 Lin ZB, "Cellular and molecular mechanisms of immunomodulationby Ganoderma lucidum" 99 : 144-153, 2005

49 Moon DO, "Buteinsuppresses the expression of nuclear factor-kappa B-mediatedmatrix metalloproteinase-9 and vascular endothelial growthfactor in prostate cancer cells" 24 : 1927-1934, 2010

50 ShinDY, "Antiinvasiveactivity of diallyl disulfide through tightening of tightjunctions and inhibition of matrix metalloproteinase activitiesin LNCaP prostate cancer cells" 24 : 1569-1576, 2010

51 YuenJW, "Anticancer effects of Ganoderma lucidum:a review of scientific evidence" 53 : 11-17, 2005

52 홍수현, "Anti-invasive activity of sanguinarine through modulation of tight junctions and matrix metalloproteinase activities in MDA-MB-231 human breast carcinoma cells" Amsterdam, Elsevier. 179 : 185-191, 2009

53 Sung Ok Kim, "Anti-invasive activity of histone deacetylase inhibitors via the induction of Egr-1 and the modulation of tight junction-related proteins in human hepatocarcinoma cells" 한국생화학분자생물학회 42 (42): 655-660, 2009