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A polypeptide from shark troponin I can inhibit angiogenesis and tumor growth

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Abstract

The shark troponin I gene (TnI) was found for the first time in this study to inhibit endothelial cell proliferation and angiogenesis. This shark TnI had 68.9% amino acid homology with human TnI, whereas the polypeptide from Lys91 to Leu123, which is thought to be the active site of TnI, had 78.8% homology with the corresponding fragment of human TnI. However, the polypeptide of shark had higher activity to inhibit the proliferation of HUVEC and tumor cell lines than that of human TnI. To investigate the anti-angiogenesis and anti-tumor effect of the shark TnI polypeptide, the DNA sequence of polypeptide (Lys91-Leu123) of white-spot catshark TnI(psTnI) was cloned and fused with the His-SUMO cDNA, followed by expression in Escherichia coli. After its purification by Ni2+ affinity chromatography, the fusion His-SUMO-psTnI protein was digested with the SUMO enzyme to release psTnI. The inhibitory ability of this recombinant shark TnI polypeptide for angiogenesis was confirmed by chicken embryo allantoic membrane (CAM) test and IHC analysis. It was also found by breast carcinoma xenograft study in Balb/c mice that this polypeptide could inhibit tumor growth in vivo.

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References

  1. Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16:159–178

    Article  PubMed  CAS  Google Scholar 

  2. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other disease. Nature 407:249–257

    Article  PubMed  CAS  Google Scholar 

  3. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186

    Article  PubMed  CAS  Google Scholar 

  4. Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6

    Article  PubMed  CAS  Google Scholar 

  5. Pandya NM, Dhalla NS, Santani DD (2006) Angiogenesis-a new target for future therapy. Vasc Pharmacol 44:265–274

    Article  CAS  Google Scholar 

  6. Zetter BR (1998) Angiogenesis and tumor metastasis. Annu Rev Med 49:407–424

    Article  PubMed  CAS  Google Scholar 

  7. Folkman J (2003) Angiogenesis inhibitors a new class of drug. Cancer Biol Ther 2(l1):S127–S133

    Google Scholar 

  8. Moses MA, Sudhalter J, Langer R (1990) Identification of an inhibitor of neovascularization from cartilage. Science 248:1408–1410

    Article  PubMed  CAS  Google Scholar 

  9. Sheu JR, Fu CC, Tsai ML, Chung WJ E (1998) Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on antiangiogenesis and anti-tumor activities. Anticancer Res 18:4435–4441

    PubMed  CAS  Google Scholar 

  10. Bukowski RM (2003) AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12:1403–1411

    Article  PubMed  CAS  Google Scholar 

  11. Dupont E, Falardeau P, Mousa SA, Dimitriadou V, Pepin MC, Wang T, Alaoui-Jamali MA (2002) Antiangiogenic and antimetastatic properties of neovastat (AE-941), an orally active extract derived from cartilage tissue. Clin Exp Metastasis 19:145–153

    Article  PubMed  CAS  Google Scholar 

  12. He L, Huang J, Shen S, Sun S (2005) Anti-tumor substances of shark and their action mechanisms. Mar Sci 29:63–66

    CAS  Google Scholar 

  13. Cho JJ, Kim YT (2002) Sharks: a potential source of antiangiogenesis factors and tumor treatment. Mar Biotechnol 4:521–525

    Article  PubMed  CAS  Google Scholar 

  14. Gonzalez RP, Leyva A, Moraes MO (2001) Shark cartilage as source of antiangiogenic compounds: from basic to clinical research. Biol Pharm Bull 24:1097–1101

    Article  PubMed  CAS  Google Scholar 

  15. Lee A, Langer R (1983) Shark cartilage contains inhibitors of tumor angiogenesis. Science 221:1185–1187

    Article  PubMed  CAS  Google Scholar 

  16. Langer R, Brem H, Falterman K, Klein M, Folkman J (1976) Isolation of a cartilage factor that inhibits tumor neovascularizatio. Science 193:70–72

    Article  PubMed  CAS  Google Scholar 

  17. Oikawa T, Ashino-Fuse H, Shimamura M, Koide U, Iwaguchi T (1990) A novel angiogenic inhibitor derived from Japanese shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Cancer Lett 51:181–186

    Article  PubMed  CAS  Google Scholar 

  18. Beliveau R, Gingras D, Kruger EA, Lamy S, Sirois P, Simard B, Sirois MG, Tranqui L, Baffert R, Beaulieu E, Dimitriadou V, Pepin M-C, Courjal F, Ricard I, Poyet P, Falardeau P, Figg WD, Dupont E (2002) The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects. Clin Cancer Res 8:1242–1250

    PubMed  CAS  Google Scholar 

  19. Berbari P, Thibodeau A, Germain L, Saint-Cyr M, Gaudreau P, El-Khouri S, Dupont E, Garrel DR (1999) Antiangiogenic effects of the oral administration of liquid cartilage extract in humans. J Surg Res 87:108–113

    Article  PubMed  CAS  Google Scholar 

  20. Hassan ZM, Reza F, Sheikhian A, Bargahi A, Mostafaie A, Manosouri K, Shahrokhi S, Ghazanfari T, Shahabi S (2005) Low molecular weight fraction of shark cartilage can modulate immune response and abolish angiogenesis. Int Immunopharmacol 5:961–970

    Article  PubMed  CAS  Google Scholar 

  21. Kim JT, Kim KS, Bae M, Song HS, Ahn MY, Kim Y, Lee S, Kim KW (2001) Cloning and characterization of tissue inhibitor of metalloproteinase-3(TIMP-3) from shark, Scyliorhinus torazame. Biochem Biophys Acta 1517:311–315

    PubMed  CAS  Google Scholar 

  22. Reza F, Hassan ZM, Mostafaie A (2003) Modulation of CD4 and CD8+tumor infilitrating lymphocytes by a fraction isolated from shark cartilage: shark cartilage modulate anti-tumor immunity. Int Immunopharmacol 3:921–926

    Article  Google Scholar 

  23. Syska H, Wilkinson JM, Grand RJ, Perry SV (1976) The relationship between biological activity and primary structure of troponin I from white skeletal muscle of the rabbit. Biochem J 53:375–387

    Google Scholar 

  24. Zhu L, Perez-Alvarado G, Wade R (1994) Sequencing of a cDNA encoding the human fast-twitch skeletal muscle isoform of troponin I. Biochim Biophys Acta 1217:338–340

    PubMed  CAS  Google Scholar 

  25. Singh SV, Powolny AA, Stan SD, Xiao D, Arlotti JA, Warin R, Hahm ER, Marynowski SW, Bommareddy A, Potter DM, Dhir R (2008) Garlic constituent diallyl trisulfide prevents development of poorly differentiated prostate cancer and pulmonary metastasis multiplicity in TRAMP mice. Cancer Res 68:9503–9511

    Article  PubMed  CAS  Google Scholar 

  26. Li Q, Liu Y, Shen PY, Dai X-Q, Wang S, Smillie LB, Sandford R, Chen X-Z (2003) Troponin I binds polycystin-L and inhibits its calcium-induced channel activation. Biochemistry 42:7618–7625

    Article  PubMed  CAS  Google Scholar 

  27. Li Q, Shen PY, Wu G, Chen X-Z (2003) Polycystin-2 interacts with Troponin I, an angiogenesis inhibitor. Biochemistry 42:450–457

    Article  PubMed  CAS  Google Scholar 

  28. Moses MA, Wiederschain D, Wu I, Fernandez CA, Ghazizdeh V, Lane WS, Flynn E, Sytkowki A, Tao T, Langer R (1999) Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci USA 96:2645–2650

    Article  PubMed  CAS  Google Scholar 

  29. Schmidt K, Hoffend J, Altmann A, Kiessling F, Strauss L, Koczan D, Mier W, Eisenhut M, Kinscherf R, Haberkorn U (2006) Troponin I overexpression inhibits tumor growth, perfusion, and vascularization of Morris hepatoma. J Nuclear Med 4:1506–1514

    Google Scholar 

  30. Xiong GW, Li Y, Wei YQ, Wang SL, Ling T, Lei S, Kan B, Mao YQ (2007) Expression of the human fast-twitch skeletal muscle troponin I cDNA in a human ovarian carcinoma suppresses tumor growth. Sci China Ser C 50:93–100

    Article  CAS  Google Scholar 

  31. Dutour A, Rabinovich-Chable H, Kaletta C, Michaelis U, Fiorenza F, Sturtz F, Rigaud M (2004) Is troponin I gene therapy effective for osteosarcoma treatment? Study on a human-like orthotopic rat model. Anticancer Res 24:3977–3982

    PubMed  CAS  Google Scholar 

  32. Fukumoto S, Sakaguchi T, You M, Xuan X, Fujisaki K (2006) Tick troponin I-like molecule is a potent inhibitor for angiogenesis. Microvascr Res 71:218–221

    Article  CAS  Google Scholar 

  33. Kern BE, Balcom JH, Antoniu BA, Warshaw AL, Castillo CF (2003) Troponin I peptide (Glu94-Leu123), a cartilage-derived angiogenesis inhibitor: in vitro and in vivo effects on human endothelial cells and on pancreatic cancer. J Gastrointest Surg 7:961–968

    Article  PubMed  Google Scholar 

  34. Feldman L, Rouleau C (2002) Troponin I inhibits capillary endothelial cell proliferation by interaction with the cell’s bfgf receptor. Microvasc Res 63:41–49

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. Huang Yadong to offer us the gene of SUMO. We are very grateful for the help of Dr. Su Zhijian on the purification of psTnI and for the revision of this article by Prof. Cai Dongqing and Prof. Wei Xing. This study was supported by 211 Grant of MOE of China.

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Correspondence to Xu-Fang Liang or An Hong.

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Xie, Q., Yao, S., Chen, X. et al. A polypeptide from shark troponin I can inhibit angiogenesis and tumor growth. Mol Biol Rep 39, 1493–1501 (2012). https://doi.org/10.1007/s11033-011-0887-y

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  • DOI: https://doi.org/10.1007/s11033-011-0887-y

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