The hexane fraction of Naematoloma sublateritium extract suppresses the TNF-α-induced metastatic potential of MDA-MB-231 breast cancer cells through modulation of the JNK and p38 pathways

Lee,Yu  Ran; Kim,Ki Mo; Jeon,Byeong  Hwa; Choi,Sunga

doi:10.3892/ijo.2014.2526

The hexane fraction of Naematoloma sublateritium extract suppresses the TNF-α-induced metastatic potential of MDA-MB-231 breast cancer cells through modulation of the JNK and p38 pathways

Authors:
- Yu Ran Lee
- Ki Mo Kim
- Byeong Hwa Jeon
- Sunga Choi
View Affiliations

Affiliations: Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301747, Republic of Korea, Cancer Research Team, Korean Medicine Based Herbal Drug Research Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon 305811, Republic of Korea
Published online on: June 27, 2014 https://doi.org/10.3892/ijo.2014.2526
Pages: 1284-1292

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Naematoloma sublateritium (Fr.) P. Karst is a basidiomycete that has been used as traditional medicine. N. sublateritium produces a triterpenoid antitumor compound, clavaric acid, but, in general, the effects of N. sublateritium constituents against tumor invasion and metastasis have been poorly studied. To investigate the inhibitory effect of N. sublateritium constituents on highly invasive and metastatic tumor cells, the TNF-α-stimulated human breast cancer cell line, MDA-MB‑231 was treated with the hexane fraction of an N. sublateritium extract (HFNS). Non-cytotoxic concentrations of HFNS markedly inhibited the invasion and migration of the MDA-MB‑231 cells in the Matrigel invasion assay and wound-healing analysis, respectively. Gelatin zymography showed that HFNS suppressed the activity of MMP-9, but not of MMP-2. Immunoblotting demonstrated that treatment with HFNS had decreased the level of MMP-9 and urokinase plasminogen activator-1 (uPA-1), but had upregulated expression of the endogenous inhibitor proteins, including TIMP-1,-2, and PAI-1, in a dose-dependent manner. Furthermore, HFNS suppressed the phosphorylation of p38 and JNK1/2, but not that of ERK1/2. This was confirmed by pretreatment of cells with specific inhibitors prior to stimulation with TNF-α. HFNS treatment also led to a dose-dependent inhibition of the DNA-binding activities of AP-1 and NFκB, which are downstream targets of JNK and p38. These data suggested that HFNS inhibits the metastatic potential of MDA-MB‑231 cells by inhibiting the phosphorylation of JNK/p38 and reducing AP-1 and NFκB DNA-binding activities. Therefore, HFNS may be a potential therapeutic agent against metastasis of breast cancer.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Kreusel KM, Bechrakis NE, Wiegel T, Krause L and Foerster MH: Incidence and clinical characteristics of symptomatic choroidal metastasis from lung cancer. Acta Ophthalmol. 86:515–519. 2008. View Article : Google Scholar : PubMed/NCBI
3	Yang HL, Kuo YH, Tsai CT, et al: Anti-metastatic activities of Antrodia camphorata against human breast cancer cells mediated through suppression of the MAPK signaling pathway. Food Chem Toxicol. 49:290–298. 2011. View Article : Google Scholar
4	Fidler IJ: Orthotopic implantation of human colon carcinomas into nude mice provides a valuable model for the biology and therapy of metastasis. Cancer Metastasis Rev. 10:229–243. 1991. View Article : Google Scholar : PubMed/NCBI
5	Yilmaz M, Christofori G and Lehembre F: Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med. 13:535–541. 2007. View Article : Google Scholar : PubMed/NCBI
6	Sliva D, English D, Lyons D and Lloyd FP Jr: Protein kinase C induces motility of breast cancers by upregulating secretion of urokinase-type plasminogen activator through activation of AP-1 and NF-kappaB. Biochem Biophys Res Commun. 290:552–557. 2002. View Article : Google Scholar
7	Zheng H, Takahashi H, Murai Y, et al: Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma. Anticancer Res. 26:3579–3583. 2006.PubMed/NCBI
8	Westermarck J and Kahari VM: Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 13:781–792. 1999.PubMed/NCBI
9	Quaranta M, Daniele A, Coviello M, et al: MMP-2, MMP-9, VEGF and CA 15.3 in breast cancer. Anticancer Res. 27:3593–3600. 2007.
10	Folgueras AR, Pendas AM, Sanchez LM and Lopez-Otin C: Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int J Dev Biol. 48:411–424. 2004. View Article : Google Scholar : PubMed/NCBI
11	Look M, van Putten W, Duffy M, et al: Pooled analysis of prognostic impact of uPA and PAI-1 in breast cancer patients. Thromb Haemost. 90:538–548. 2003.PubMed/NCBI
12	Rosen EM, Goldberg ID, Liu D, et al: Tumor necrosis factor stimulates epithelial tumor cell motility. Cancer Res. 51:5315–5321. 1991.PubMed/NCBI
13	Hagemann T, Wilson J, Kulbe H, et al: Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol. 175:1197–1205. 2005. View Article : Google Scholar : PubMed/NCBI
14	Chazaud B, Ricoux R, Christov C, Plonquet A, Gherardi RK and Barlovatz-Meimon G: Promigratory effect of plasminogen activator inhibitor-1 on invasive breast cancer cell populations. Am J Pathol. 160:237–246. 2002. View Article : Google Scholar : PubMed/NCBI
15	Stetler-Stevenson WG: Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal. 1:re62008. View Article : Google Scholar
16	Lijnen HR: Pleiotropic functions of plasminogen activator inhibitor-1. J Thromb Haemost. 3:35–45. 2005. View Article : Google Scholar : PubMed/NCBI
17	Rose P, Huang Q, Ong CN and Whiteman M: Broccoli and watercress suppress matrix metalloproteinase-9 activity and invasiveness of human MDA-MB-231 breast cancer cells. Toxicol Appl Pharmacol. 209:105–113. 2005. View Article : Google Scholar : PubMed/NCBI
18	Choi S and Singh SV: Bax and Bak are required for apoptosis induction by sulforaphane, a cruciferous vegetable-derived cancer chemopreventive agent. Cancer Res. 65:2035–2043. 2005. View Article : Google Scholar : PubMed/NCBI
19	Ho YC, Yang SF, Peng CY, Chou MY and Chang YC: Epigallocatechin-3-gallate inhibits the invasion of human oral cancer cells and decreases the productions of matrix metalloproteinases and urokinase-plasminogen activator. J Oral Pathol Med. 36:588–593. 2007. View Article : Google Scholar : PubMed/NCBI
20	Seo HS, DeNardo DG, Jacquot Y, et al: Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha. Breast Cancer Res Treat. 99:121–134. 2006. View Article : Google Scholar : PubMed/NCBI
21	Jiang J, Grieb B, Thyagarajan A and Sliva D: Ganoderic acids suppress growth and invasive behavior of breast cancer cells by modulating AP-1 and NF-kappaB signaling. Int J Mol Med. 21:577–584. 2008.PubMed/NCBI
22	Sliva D, Jedinak A, Kawasaki J, Harvey K and Slivova V: Phellinus linteus suppresses growth, angiogenesis and invasive behaviour of breast cancer cells through the inhibition of AKT signalling. Br J Cancer. 98:1348–1356. 2008. View Article : Google Scholar
23	Kim HG, Yoon DH, Lee WH, et al: Phellinus linteus inhibits inflammatory mediators by suppressing redox-based NF-kappaB and MAPKs activation in lipopolysaccharide-induced RAW 264.7 macrophage. J Ethnopharmacol. 114:307–315. 2007. View Article : Google Scholar
24	Godio RP, Fouces R, Gudina EJ and Martin JF: Agrobacterium tumefaciens-mediated transformation of the antitumor clavaric acid-producing basidiomycete Hypholoma sublateritium. Curr Genet. 46:287–294. 2004. View Article : Google Scholar
25	Godio RP, Fouces R and Martin JF: A squalene epoxidase is involved in biosynthesis of both the antitumor compound clavaric acid and sterols in the basidiomycete H. sublateritium. Chem Biol. 14:1334–1346. 2007. View Article : Google Scholar : PubMed/NCBI
26	Godio RP and Martin JF: Modified oxidosqualene cyclases in the formation of bioactive secondary metabolites: biosynthesis of the antitumor clavaric acid. Fungal Genet Biol. 46:232–242. 2009. View Article : Google Scholar : PubMed/NCBI
27	Choi S, Jang HJ, Choi JY, Kim MS, Lee YR, Kim HS, Choi SW, Jeon BH, Won SI, Kim TW and Choi JW: Antioxidant and anticancer activity of fractions of the ethanol extract of Naematoloma sublateritium. J Med Plants Res. 6:92012.
28	Lee YR, Kim KM, Jeon BH, Choi JW and Choi S: The n-butanol fraction of Naematoloma sublateritium suppresses the inflammatory response through downregulation of NF-kappaB in human endothelial cells. Int J Mol Med. 29:801–808. 2012.
29	Kajanne R, Miettinen P, Mehlem A, et al: EGF-R regulates MMP function in fibroblasts through MAPK and AP-1 pathways. J Cel Physiol. 212:489–497. 2007. View Article : Google Scholar : PubMed/NCBI
30	Cohen M, Meisser A, Haenggeli L and Bischof P: Involvement of MAPK pathway in TNF-alpha-induced MMP-9 expression in human trophoblastic cells. Mol Hum Reprod. 12:225–232. 2006. View Article : Google Scholar : PubMed/NCBI
31	Leber TM and Balkwill FR: Regulation of monocyte MMP-9 production by TNF-alpha and a tumour-derived soluble factor (MMPSF). Br J Cancer. 78:724–732. 1998. View Article : Google Scholar : PubMed/NCBI
32	Stuelten CH, DaCosta Byfield S, Arany PR, Karpova TS, Stetler-Stevenson WG and Roberts AB: Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-alpha and TGF-beta. J Cell Sci. 118:2143–2153. 2005. View Article : Google Scholar : PubMed/NCBI
33	Bachmeier BE, Nerlich AG, Lichtinghagen R and Sommerhoff CP: Matrix metalloproteinases (MMPs) in breast cancer cell lines of different tumorigenicity. Anticancer Res. 21:3821–3828. 2001.PubMed/NCBI
34	John A and Tuszynski G: The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res. 7:14–23. 2001. View Article : Google Scholar : PubMed/NCBI
35	Lee EJ, Kim WJ and Moon SK: Cordycepin suppresses TNF-alpha-induced invasion, migration and matrix metalloproteinase-9 expression in human bladder cancer cells. Phytother Res. 24:1755–1761. 2010. View Article : Google Scholar : PubMed/NCBI
36	Yaoita Y, Matsuki K, Iijima T, et al: New sterols and triterpenoids from four edible mushrooms. Chem Pharm Bull. 49:589–594. 2001. View Article : Google Scholar : PubMed/NCBI
37	Chavez KJ, Garimella SV and Lipkowitz S: Triple negative breast cancer cell lines: one tool in the search for better treatment of triple negative breast cancer. Breast Dis. 32:35–48. 2010.PubMed/NCBI