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Effects of an engineered anti-HER2 antibody chA21 on invasion of human ovarian carcinoma cell in vitro

  • Original Article
  • Published:
Chinese Journal of Cancer Research

Abstract

Objective

HER-2 plays an important role in the development and progression of ovarian carcinoma. A number of monoclonal antibodies (MAbs) and engineered antibody fragments (such as scFvs) against the subdomain II or IV of HER-2 extracellular domain (ECD) have been developed. We investigated the effect of chA21, an engineered anti-HER-2 antibody that bind primarily to subdomain I, on ovarian carcinoma cell invasion in vitro, and explored its possible mechanisms.

Methods

Growth inhibition of SK-OV-3 cells was assessed using a Methyl thiazolyl tetrazolium (MTT) assay. The invasion ability of SK-OV-3 was determined by a Transwell invasion assay. The expression of matrix metalloproteinase-2 (MMP-2) and its tissue inhibitors (TIMP-2) was detected by immunocytochemical staining, and the expression of p38 and the phosphorylation of p38 were assayed by both immunocytochemistry and Western blot.

Results

After treatment with chA21, the invasion of human ovarian cancer SK-OV-3 cells was inhibited in dose- and time-dependent manners. Simultaneously the expression of p38, phospho-p38, MMP-2 and the MMP-2/TIMP-2 ratio decreased, while TIMP-2 expression increased. Additionally, the decrease in phospho-p38 was much greater than that of p38.

Conclusion

chA21 may inhibit SK-OV-3 cell invasion via the signal transduction pathway involving MMP-2, TIMP-2, p38 and the activation of p38MAPK.

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Reference

  1. Carpenter G. Receptors of epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem 1987; 56: 881–914.

    Article  PubMed  CAS  Google Scholar 

  2. Verri E, Guglielmini P, Puntoni M, et al. HER2/neu oncoprotein overexpression in epithelial ovarian cancer: evaluation of its prevalence and prognostic significance. Clinical study 2005; 68: 154–161.

    CAS  Google Scholar 

  3. Garoufali A, Kyriakou F, Kountourakis P. Extracellular domain of HER2: a useful marker for the initial workup and follow-up of HER2-positive breast cancer. J BUON 2008; 13: 409–413.

    PubMed  CAS  Google Scholar 

  4. Bramwell VH, Doig GS, Tuck AB. Changes over time of extracellular domain of HER2 (ECD/HER2) serum levels have prognostic value in metastatic breast cancer. Breast Cancer Res Treat 2009; 114: 503–511.

    Article  PubMed  CAS  Google Scholar 

  5. Garrett JT, Rawale S, Allen SD, et al. Novel engineered trastuzumab conformational epitopes demonstrate in vitro and in vivo antitumor properties against HER-2/neu. J Immunol 2007; 178: 7120–7131.

    PubMed  CAS  Google Scholar 

  6. Liu CY, Yang W, Li JF. Effect of trastuzumab on tumor cell lines shedding high or low level of HER-2 ECD. Zhonghua Zhong Liu Za Zhi 2007; 29: 101–105.

    PubMed  Google Scholar 

  7. Lurje G, Lenz HJ. EGFR Signaling and Drug Discovery. Oncology 2009; 77: 400–410.

    Article  PubMed  CAS  Google Scholar 

  8. Dean-Colomb W, Esteva FJ. Her2-positive breast cancer: herceptin and beyond. Eur J Cancer 2008; 44: 2806–2812.

    Article  PubMed  CAS  Google Scholar 

  9. Shepard HM, Jin P, Slamon DJ, et al. Herceptin. Handb Exp Pharmacol 2008; 181: 183–219.

    Article  PubMed  CAS  Google Scholar 

  10. Nahta R, Esteva FJ. HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res 2006; 8: 215.

    Article  PubMed  Google Scholar 

  11. Piccart M. Circumventing de novo and acquired resistance to trastuzumab: new hope for the care of ErbB2-positive breast cancer. Clin Breast Cancer 2008; Suppl 3: S100–S113.

    Article  Google Scholar 

  12. Dieras V, Vincent-Salomon A, Degeorges A. Trastuzumab (Herceptin) and breast cancer: mechanisms of resistance. Bull Cancer(in French) 2007; 94: 259–266.

    CAS  Google Scholar 

  13. Wilken JA, Webster KT, Maihle NJ. Trastuzumab Sensitizes Ovarian Cancer Cells to EGFR-targeted Therapeutics. J Ovarian Res 2010; 3: 7.

    Article  PubMed  Google Scholar 

  14. Abuharbeid S, Apel J, Zugmaier G, et al. Inhibition of HER-2 by three independent targeting strategies increases paclitaxel resistance of SKOV-3 ovarian carcinoma cells. Naunyn Schmiedebergs Arch Pharmacol 2005; 371: 141–151.

    Article  PubMed  CAS  Google Scholar 

  15. Hattori K, Nishi Y, Nakamura S, et al. Evaluation of cardiac dysfunction after herceptin treatment in patients with metastatic breast cancer by echocardiography. Rinsho Byori 2007; 55: 120–125.

    PubMed  Google Scholar 

  16. Takai N, Jain A, Kawamata N, et al. 2C4, a monoclonal antibody against HER2, disrupts the HER kinase signaling pathway and inhibits ovarian carcinoma cell growth. Cancer 2005; 104: 2701–2708.

    Article  PubMed  CAS  Google Scholar 

  17. Cheng LS, Liu AP, Yang JH, et al. Construction, expression and characterization of the engineered antibody against tumor surface antigen, p185(c-erbB-2). Cell Res 2003; 13: 35–48.

    Article  PubMed  CAS  Google Scholar 

  18. Hu S, Zhu Z, Li L, et al. Epitope mapping and structural analysis of an anti-ErbB2 antibody A21: Molecular basis for tumor inhibitory mechanism. Proteins 2008; 70: 938–949.

    Article  PubMed  CAS  Google Scholar 

  19. Zhang A, Xue H, Ling X, et al. Anti-HER-2 engineering antibody ChA21 inhibits growth and induces apoptosis of SK-OV-3 cells. J Exp Clin Cancer Res 2010; 29: 23.

    Article  PubMed  Google Scholar 

  20. Kim IY, Yong HY, Kang KW, et al. Overexpression of ErbB2 induces invasion of MCF10A human breast epithelial cells via MMP-9. Cancer Lett 2009; 275: 227–233.

    Article  PubMed  CAS  Google Scholar 

  21. Desmedt C, Haibe-Kains B, Wirapati P, et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res 2008; 14: 5158–5165.

    Article  PubMed  CAS  Google Scholar 

  22. Zhang SL, Lu YM, Meng LR, et al. Inhibition of invasive and chemotactic abilities of SK-OV-3 cells by human epithelial growth receptor-2 small interfering RNA. Zhonghua Fu Chan Ke Za Zhi (in Chinese) 2007; 42: 48–53.

    Google Scholar 

  23. Bradham C, McClay DR. p38 MAPK in development and cancer. Cell Cycle 2006; 5: 824–828.

    Article  PubMed  CAS  Google Scholar 

  24. Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 2007; 1773: 1358–1375.

    Article  PubMed  CAS  Google Scholar 

  25. Humar M, Loop T, Schmidt R, et al. The mitogen-activated protein kinase p38 regulates activator protein 1 by direct phosphorylation of c-Jun. Int J Biochem Cell Biol 2007; 39: 2278–2288.

    Article  PubMed  CAS  Google Scholar 

  26. Fisher GJ, Talwar HS, Lin JY, et al. Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo. J Clin Invest 1998; 101: 1432–1440.

    Article  PubMed  CAS  Google Scholar 

  27. Shen KH, Hung SH, Yin LT, et al. Acacetin, a flavonoid, inhibits the invasion and migration of human prostate cancer DU145 cells via inactivation of the p38 MAPK signaling pathway. Mol Cell Biochem 2010; 333: 279–291.

    Article  PubMed  CAS  Google Scholar 

  28. Judith A. Matrix Metalloproteinases as Mediators of Primary and Secondary Cataracts. Expert Rev Ophthalmol. 2007; 2: 931–938.

    Article  Google Scholar 

  29. Brun JL, Cortez A, Commo F. Serous and mucinous ovarian tumors express different profiles of MMP-2, -7, -9, MT1-MMP, and TIMP-1 and -2. Int J Oncol 2008; 33: 1239–1246.

    PubMed  CAS  Google Scholar 

  30. Chernov AV, Sounni NE, Remacle AG, et al. Epigenetic control of the invasion-promoting MT1-MMP/MMP-2/TIMP-2 axis in cancer cells. J Biol Chem 2009; 284: 12727–12734.

    Article  PubMed  CAS  Google Scholar 

  31. Kim TJ, Rho SB Choi YL, et al. High expression of tissue inhibitor of metalloproteinase-2 in serous ovarian carcinomas and the role of this expression in ovarian tumorigenesis. Hum Pathol 2006; 37: 906–913.

    Article  PubMed  CAS  Google Scholar 

  32. Jinga DC, Blidaru A, Condrea I. MMP-9 and MMP-2 gelatinases and TIMP-1 and TIMP-2 inhibitors in breast cancer: correlations with prognostic factors. J Cell Mol Med 2006; 10: 499–510.

    Article  PubMed  CAS  Google Scholar 

  33. Jezierska A, Motyl T. Matrix metalloproteinase-2 involvement in breast cancer progression: a mini-review. Med Sci Monit 2009; 15: RA32–RA40.

    PubMed  CAS  Google Scholar 

  34. Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2001; 2: 127–137.

    Article  PubMed  CAS  Google Scholar 

  35. Kumar B, Koul S, Petersen J, et al. p38 mitogen-activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Res 2010; 70: 832–841.

    Article  PubMed  CAS  Google Scholar 

  36. Ke Z, Lin H, Fan Z, et al. MMP-2 mediates ethanol-induced invasion of mammary epithelial cells over-expressing ErbB2. Int J Cancer 2006; 119: 8–16.

    Article  PubMed  CAS  Google Scholar 

  37. Lee EK, Lee YS, Lee H, et al. 14-3-3epsilon protein increases matrix metalloproteinase-2 gene expression via p38 MAPK signaling in NIH3T3 fibroblast cells. Exp Mol Med 2009; 41: 453–561.

    Article  PubMed  CAS  Google Scholar 

  38. Yang YT, Weng CJ, Ho CT. Resveratrol analog-3,5,4′-trimethoxytrans-stilbene inhibits invasion of human lung adenocarcinoma cells by suppressing the MAPK pathway and decreasing matrix metalloproteinase-2 expression. Mol Nutr Food Res 2009; 53: 407.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Anhui Medical University, Hefei, 230032, China

    Yi Gao, Qiang Wu, Zheng-sheng Wu, Gui-hong Zhang & An-li Zhang

Authors
  1. Yi Gao
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  2. Qiang Wu
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  3. Zheng-sheng Wu
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  4. Gui-hong Zhang
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  5. An-li Zhang
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Corresponding author

Correspondence to Qiang Wu.

Additional information

This work was supported by National “863” High-Tech R & D Program of China (No. 2004AA215260), Science Foundation for Young Teacher of Anhui Province (No.2008jq1062) and Research Foundation for Advanced Talents of the No.2 Hospital affiliated to the Anhui Medical University (No. 2009-08)

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Gao, Y., Wu, Q., Wu, Zs. et al. Effects of an engineered anti-HER2 antibody chA21 on invasion of human ovarian carcinoma cell in vitro . Chin. J. Cancer Res. 23, 147–152 (2011). https://doi.org/10.1007/s11670-011-0147-7

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  • DOI: https://doi.org/10.1007/s11670-011-0147-7

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