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Involvement of Matrix Metalloproteinases on the Inhibition of Cells Invasion and Migration by Emodin in Human Neuroblastoma SH-SY5Y Cells

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Abstract

Emodin (1,3,8-trihydroxy-6-methylanthaquinone), an active component present in the root and rhizome of Rheum palmatum L. (Polygonaceae) has anti-bacterial, anti-tumor, diuretic and vasorelaxant effects. However, its mechanism of action on the cell migration and invasion of human neuroblastoma cancer SH-SY5Y cells is not fully understood. In this study, firstly, the effects of emodin on the percentage of viable cells were examined by using MTT assay and it was found that emodin induced dose-and time-dependent inhibition in human neuroblastoma SH-SY5Y cells. Second, the effects of emodin on the migration and invasion of SH-SY5Y cells were examined by using wound assay and matrigel counting and the results showed that emodin suppressed the migration and invasion of SH-SY5Y cells. Third, we examined the effect of emodin on the levels of associated proteins by using Western blotting and the results indicated that emodin inhibited the levels of GRB2, RhoA, HIF-1α, VEGF, FAK, iNOS, COX2, p-p38, p-c-jun, MMP2, MMP9 and MMP7 but promoted the levels of PKC, PI3K, MEKK3 and NF-κB p65 that led to the inhibition of migration and invasion of SH-SY5Y cells in vitro.

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References

  1. Entschladen F, Drell TLt, Lang K, Joseph J, Zaenker KS (2004) Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters. Lancet Oncol 5:254–258. doi:10.1016/S1470-2045(04)01431-7

    Article  PubMed  CAS  Google Scholar 

  2. Sporn MB (1996) The war on cancer. Lancet 347:1377–1381. doi:10.1016/S0140-6736(96)91015-6

    Article  PubMed  CAS  Google Scholar 

  3. Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS (2004) Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 430:1034–1039

    Article  PubMed  CAS  Google Scholar 

  4. Giese A, Bjerkvig R, Berens ME, Westphal M (2003) Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 21:1624–1636. doi:10.1200/JCO.2003.05.063

    Article  PubMed  CAS  Google Scholar 

  5. Haga A, Funasaka T, Niinaka Y, Raz A, Nagase H (2003) Autocrine motility factor signaling induces tumor apoptotic resistance by regulations Apaf-1 and Caspase-9 apoptosome expression. Int J Cancer 107:707–714. doi:10.1002/ijc.11449

    Article  PubMed  CAS  Google Scholar 

  6. Lefranc F, Brotchi J, Kiss R (2005) Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 23:2411–2422. doi:10.1200/JCO.2005.03.089

    Article  PubMed  CAS  Google Scholar 

  7. Liang JW, Hsiu SL, Huang HC, Lee Chao PD (1993) HPLC analysis of emodin in serum, herbs and Chinese herbal prescriptions. J Food Drug Anal 09:251–257

    Google Scholar 

  8. Tsai TH, Chen CF (1992) Ultraviolet spectrum identification of emodin in rabbit plasma by HPLC and its pharmacokinetics application Asia Pacific. J Pharmacol 7:53–56

    CAS  Google Scholar 

  9. Huang HC, Chu SH, Chao PD (1991) Vasorelaxants from Chinese herbs, emodin and scoparone, possess immunosuppressive properties. Eur J Pharmacol 198:211–213. doi:10.1016/0014-2999(91)90624-Y

    Article  PubMed  CAS  Google Scholar 

  10. Koyama M, Kelly TR, Watanabe KA (1988) Novel type of potential anticancer agents derived from chrysophanol and emodin. Some structure-activity relationship studies. J Med Chem 31:283–284. doi:10.1021/jm00397a002

    Article  PubMed  CAS  Google Scholar 

  11. Zhou XM, Chen QH (1988) Biochemical study of Chinese rhubarb. XXII. Inhibitory effect of anthraquinone derivatives on Na+-K+-ATPase of the rabbit renal medulla and their diuretic action. Yao Xue Xue Bao 23:17–20

    PubMed  CAS  Google Scholar 

  12. Huang Q, Shen HM, Ong CN (2004) Inhibitory effect of emodin on tumor invasion through suppression of activator protein-1 and nuclear factor-kappaB. Biochem Pharmacol 68:361–371. doi:10.1016/j.bcp.2004.03.032

    Article  PubMed  CAS  Google Scholar 

  13. Wang C, Wu X, Chen M, Duan W, Sun L, Yan M et al (2007) Emodin induces apoptosis through caspase 3-dependent pathway in HK-2 cells. Toxicology 231:120–128. doi:10.1016/j.tox.2006.11.064

    Article  PubMed  CAS  Google Scholar 

  14. Brown M, Bellon M, Nicot C (2007) Emodin and DHA potently increase arsenic trioxide interferon-alpha-induced cell death of HTLV-I-transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1. Blood 109:1653–1659

    Article  PubMed  CAS  Google Scholar 

  15. Wang R, Wan Q, Zhang Y, Huang F, Yu K, Xu D et al (2007) Emodin suppresses interleukin-1beta induced mesangial cells proliferation and extracellular matrix production via inhibiting P38 MAPK. Life Sci 80:2481–2488. doi:10.1016/j.lfs.2007.04.010

    Article  PubMed  CAS  Google Scholar 

  16. Hsu SC, Kuo CL, Lin JP, Lee JH, Lin CC, Su CC et al (2007) Crude extracts of Euchresta formosana radix inhibit invasion and migration of human hepatocellular carcinoma cells. Anticancer Res 27:2377–2384

    PubMed  CAS  Google Scholar 

  17. Fishman DA, Liu Y, Ellerbroek SM, Stack MS (2001) Lysophosphatidic acid promotes matrix metalloproteinase (MMP) activation and MMP-dependent invasion in ovarian cancer cells. Cancer Res 61:3194–3199

    PubMed  CAS  Google Scholar 

  18. Huang YT, Hwang JJ, Lee LT, Liebow C, Lee PP, Ke FC et al (2002) Inhibitory effects of a luteinizing hormone-releasing hormone agonist on basal and epidermal growth factor-induced cell proliferation and metastasis-associated properties in human epidermoid carcinoma A431 cells. Int J Cancer 99:505–513. doi:10.1002/ijc.10373

    Article  PubMed  CAS  Google Scholar 

  19. Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC (1997) The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 137:1445–1457. doi:10.1083/jcb.137.6.1445

    Article  PubMed  CAS  Google Scholar 

  20. Kwak HJ, Park MJ, Park CM, Moon SI, Yoo DH, Lee HC et al (2006) Emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by blocking receptor-2 (KDR/Flk-1) phosphorylation. Int J Cancer 118:2711–2720. doi:10.1002/ijc.21641

    Article  PubMed  CAS  Google Scholar 

  21. Lu Y, Zhang J, Qian J (2008) The effect of emodin on VEGF receptors in human colon cancer cells. Cancer Biother Radiopharm 23:222–228. doi:10.1089/cbr.2007.0425

    Article  PubMed  CAS  Google Scholar 

  22. Cha TL, Qiu L, Chen CT, Wen Y, Hung MC (2005) Emodin down-regulates androgen receptor and inhibits prostate cancer cell growth. Cancer Res 65:2287–2295. doi:10.1158/0008-5472.CAN-04-3250

    Article  PubMed  CAS  Google Scholar 

  23. Huang HC, Lee CR, Chao PD, Chen CC, Chu SH (1991) Vasorelaxant effect of emodin, an anthraquinone from a Chinese herb. Eur J Pharmacol 205:289–294. doi:10.1016/0014-2999(91)90912-A

    Article  PubMed  CAS  Google Scholar 

  24. Cai J, Razzak A, Hering J, Saed A, Babcock TA, Helton S et al (2008) Feasibility evaluation of emodin (rhubarb extract) as an inhibitor of pancreatic cancer cell proliferation in vitro. JPEN J Parenter Enteral Nutr 32:190–196. doi:10.1177/0148607108314371

    Article  CAS  Google Scholar 

  25. Guo J, Xiao B, Liu Q, Gong Z, Le Y (2008) Suppression of C-myc expression associates with anti-proliferation of aloe-emodin on gastric cancer cells. Cancer Invest 26:369–374. doi:10.1080/07357900701788130

    Article  PubMed  CAS  Google Scholar 

  26. Kim HR, Kim K, Lee KH, Kim SJ, Kim J (2008) Inhibition of casein kinase 2 enhances the death ligand- and natural kiler cell-induced hepatocellular carcinoma cell death. Clin Exp Immunol 152:336–344

    Article  PubMed  CAS  Google Scholar 

  27. Wang XD, Gu LQ, Wu JY (2007) Apoptosis-inducing activity of new pyrazole emodin derivatives in human hepatocellular carcinoma HepG2 cells. Biol Pharm Bull 30:1113–1116. doi:10.1248/bpb.30.1113

    Article  PubMed  CAS  Google Scholar 

  28. Huang Q, Shen HM, Ong CN (2005) Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway. Cell Mol Life Sci 62:1167–1175. doi:10.1007/s00018-005-5050-2

    Article  PubMed  CAS  Google Scholar 

  29. Kim JH, Na HJ, Kim CK, Kim JY, Ha KS, Lee H et al (2008) The non-provitamin A carotenoid, lutein, inhibits NF-kappaB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-kappaB-inducing kinase pathways: role of H(2)O(2) in NF-kappaB activation. Free Radic Biol Med 45:885–896. doi:10.1016/j.freeradbiomed.2008.06.019

    Article  PubMed  CAS  Google Scholar 

  30. Mathes E, O’Dea EL, Hoffmann A, Ghosh G (2008) NF-kappaB dictates the degradation pathway of IkappaBalpha. EMBO J 27:1357–1367. doi:10.1038/emboj.2008.73

    Article  PubMed  CAS  Google Scholar 

  31. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev 2:563–572

    CAS  Google Scholar 

  32. Morozevich GE, Kozlova NI, Cheglakov IB, Ushakova NA, Preobrazhenskaya ME, Berman AE (2008) Implication of alpha5beta1 integrin in invasion of drug-resistant MCF-7/ADR breast carcinoma cells: a role for MMP-2 collagenase. Biochemistry 73:791–796

    PubMed  CAS  Google Scholar 

  33. Nagase H, Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274:21491–21494. doi:10.1074/jbc.274.31.21491

    Article  PubMed  CAS  Google Scholar 

  34. Stetler-Stevenson WG (1996) Dynamics of matrix turnover during pathologic remodeling of the extracellular matrix. Am J Pathol 148:1345–1350

    PubMed  CAS  Google Scholar 

  35. Rydlova M, Holubec L Jr, Ludvikova M Jr, Kalfert D, Franekova J, Povysil C et al (2008) Biological activity and clinical implications of the matrix metalloproteinases. Anticancer Res 28:1389–1397

    PubMed  CAS  Google Scholar 

  36. Park SK, Han SB, Lee K, Lee HJ, Kho YH, Chun H et al (2006) Gelastatins and their hydroxamates as dual functional inhibitors for TNF-alpha converting enzyme and matrix metalloproteinases: synthesis, biological evaluation, and mechanism studies. Biochem Biophys Res Commun 341:627–634. doi:10.1016/j.bbrc.2005.12.219

    Article  PubMed  CAS  Google Scholar 

  37. Chantrain CF, Shimada H, Jodele S, Groshen S, Ye W, Shalinsky DR et al (2004) Stromal matrix metalloproteinase-9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment. Cancer Res 64:1675–1686. doi:10.1158/0008-5472.CAN-03-0160

    Article  PubMed  CAS  Google Scholar 

  38. Ribatti D, Marimpietri D, Pastorino F, Brignole C, Nico B, Vacca A et al (2004) Angiogenesis in neuroblastoma. Ann N Y Acad Sci 1028:133–142. doi:10.1196/annals.1322.014

    Article  PubMed  CAS  Google Scholar 

  39. Ara T, Fukuzawa M, Kusafuka T, Komoto Y, Oue T, Inoue M et al (1998) Immunohistochemical expression of MMP-2, MMP-9, and TIMP-2 in neuroblastoma: association with tumor progression and clinical outcome. J Pediatr Surg 33:1272–1278. doi:10.1016/S0022-3468(98)90167-1

    Article  PubMed  CAS  Google Scholar 

  40. Cheng Y, Dong Q, Sun LR, Yang CM, Jiang BX (2005) Correlation between expression of MMP-2, MMP-9, TIMP-2, TIMP-1 and metastasis of neuroblastoma. Zhonghua Zhong Liu Za Zhi 27:164–166

    PubMed  CAS  Google Scholar 

  41. Sugiura Y, Shimada H, Seeger RC, Laug WE, DeClerck YA (1998) Matrix metalloproteinases-2 and -9 are expressed in human neuroblastoma: contribution of stromal cells to their production and correlation with metastasis. Cancer Res 58:2209–2216

    PubMed  CAS  Google Scholar 

  42. Heslin MJ, Yan J, Johnson MR, Weiss H, Diasio RB, Urist MM (2001) Role of matrix metalloproteinases in colorectal carcinogenesis. Ann Surg 233:786–792. doi:10.1097/00000658-200106000-00008

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grant CMU97-086 from China Medical University, Taichung, Taiwan, ROC.

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Authors and Affiliations

  1. Department of Clinical Pathology, Cheng Hsin Rehabilitation Medical Center, Taipei, Taiwan, ROC

    Hsu-Feng Lu

  2. College of Human Ecology, Fu-Jen University, Taipei, Taiwan, ROC

    Hsu-Feng Lu

  3. School of Medicine, China Medical University, Taichung, Taiwan, ROC

    Kuang-Chi Lai

  4. Department of Surgery, China Medical University Beigang Hospital, Yunlin, Taiwan, ROC

    Kuang-Chi Lai

  5. Department of Chinese Medicine Resources, China Medical University, Taipei, Taiwan, ROC

    Shu-Chun Hsu & Chao-Lin Kuo

  6. Department of Ophthalmology, China Medical University Hospital, Taichung, Taiwan, ROC

    Hui-Ju Lin

  7. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan, ROC

    Ching-Lung Liao

  8. Department of Pharmacology, China Medical University, Taichung, Taiwan, ROC

    Jai-Sing Yang

  9. Department of Biological Science and Technology, China Medical University, No 91, Hsueh-Shih Road, Taichung, 404, Taiwan, ROC

    Jing-Gung Chung

  10. Department of Biotechnology, Asia University, Wufeng, Taichung, Taiwan, ROC

    Jing-Gung Chung

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  1. Hsu-Feng Lu
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Correspondence to Jing-Gung Chung.

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Lu, HF., Lai, KC., Hsu, SC. et al. Involvement of Matrix Metalloproteinases on the Inhibition of Cells Invasion and Migration by Emodin in Human Neuroblastoma SH-SY5Y Cells. Neurochem Res 34, 1575–1583 (2009). https://doi.org/10.1007/s11064-009-9946-3

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