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Naphtho[1,2-b]furan-4,5-dione inhibits MDA-MB-231 cell migration and invasion by suppressing Src-mediated signaling pathways

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Abstract

Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Breast cancer is a highly malignant carcinoma and most deaths of breast cancer are caused by metastasis. In this study, we showed that NFD blocked migration and invasion of MDA-MB-231 breast cancer cells without affecting apoptosis or growth arrest. NFD caused significant block of Src kinase activity in MDA-MB-231 cells. Moreover, NFD treatment was correlated with reduced phosphorylation of FAK at Tyr 576/577, 861 and 925 sites, p130Cas at Tyr 410, and paxillin at Tyr 118. NFD also suppressed the activation of phosphatidylinositol 3-kinase/Akt. Consistent with inhibition of these signaling pathways and invasion, NFD reduced the expression of matrix metalloproteinase-9. Furthermore, Src antagonist PP2 caused a significant decrease in the phosphorylation of FAK, p130Cas, paxillin, and PI3K/Akt. Our findings provide evidences that NFD inhibits Src-mediated signaling pathways involved in controlling breast cancer migration and invasion, suggesting that it has a therapeutic potential in breast cancer treatment.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  2. Christofori G (2006) New signals from the invasive front. Nature 441:444–450

    Article  CAS  PubMed  Google Scholar 

  3. Parsons SJ, Parsons JT (2004) Src family kinases, key regulators of signal transduction. Oncogene 23:7906–7909

    Article  CAS  PubMed  Google Scholar 

  4. Yeatman TJ (2004) A renaissance for SRC. Nat Rev Cancer 4:470–480

    Article  CAS  PubMed  Google Scholar 

  5. Hiscox S, Nicholson RI (2008) Src inhibitors in breast cancer therapy. Expert Opin Ther Targets 12:757–767

    Article  CAS  PubMed  Google Scholar 

  6. Finn RS (2008) Targeting Src in breast cancer. Ann Oncol 19:1379–1386

    Article  CAS  PubMed  Google Scholar 

  7. Guarino M (2010) Src signaling in cancer invasion. J Cell Physiol 223:14–26

    CAS  PubMed  Google Scholar 

  8. Weis S, Cui J, Barnes L, Cheresh D (2004) Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol 167:223–229

    Article  CAS  PubMed  Google Scholar 

  9. Thomas SM, Brugge JS (1997) Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13:513–609

    Article  CAS  PubMed  Google Scholar 

  10. Nagaraj NS, Smith JJ, Revetta F, Washington MK, Merchant NB (2010) Targeted inhibition of SRC kinase signaling attenuates pancreatic tumorigenesis. Mol Cancer Ther 9:2322–2332

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Goulart MOF, Zani CL, Tonholo J, Freitas LR, deAbreu FC, Oliveira AB, Raslan DS, Starling S, Chiari E (1997) Trypanocidal activity and redox potential of heterocyclic- and 2-hydroxy-naphthoquinones. Bioorg Med Chem Lett 7:2043–2048

    Article  CAS  Google Scholar 

  12. Kongkathip N, Kongkathip B, Siripong P, Sangma C, Luangkamin S, Niyomdecha M, Pattanapa S, Piyaviriyagul S, Kongsaeree P (2003) Potent antitumor activity of synthetic 1,2-naphthoquinones and 1,4-naphthoquinones. Bioorg Med Chem 11:3179–3191

    Article  CAS  PubMed  Google Scholar 

  13. Sutton DC, Gillan FT, Susic M (1985) Naphthofuranone phytoalexins from the grey mangrove, Avicennia Marina. Phytochemistry 24:2877–2879

    Article  CAS  Google Scholar 

  14. Tseng CH, Lin CS, Shih PK, Tsao LT, Wang JP, Cheng CM, Tzeng CC, Chen YL (2009) Furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives as potential inhibitors of inflammatory factors in sepsis. Bioorg Med Chem 17:6773–6779

    Article  CAS  PubMed  Google Scholar 

  15. Betapudi V, Licate LS, Egelhoff TT (2006) Distinct roles of nonmuscle myosin II isoforms in the regulation of MDA-MB-231 breast cancer cell spreading and migration. Cancer Res 66:4725–4733

    Article  CAS  PubMed  Google Scholar 

  16. Lin KL, Su JC, Chien CM, Tseng CH, Chen YL, Chang LS, Lin SR (2010) Naphtho[1,2-b]furan-4,5-dione induces apoptosis and S-phase arrest of MDA-MB-231 cells through JNK and ERK signaling activation. Toxicol In Vitro 24:61–70

    Article  CAS  PubMed  Google Scholar 

  17. Liu X, Feng R (2010) Inhibition of epithelial to mesenchymal transition in metastatic breast carcinoma cells by c-Src suppression. Acta Biochim Biophys Sin 42:496–501

    Article  CAS  PubMed  Google Scholar 

  18. Ma JG, Huang H, Chen SM, Chen Y, Xin XL, Lin LP, Ding J, Liu H, Meng LH (2011) PH006, a novel and selective Src kinase inhibitor, suppresses human breast cancer growth and metastasis in vitro and in vivo. Breast Cancer Res Treat 130:85–96

    Article  CAS  PubMed  Google Scholar 

  19. Sharma A, Mayer BJ (2008) Phosphorylation of p130Cas initiates Rac activation and membrane ruffling. BMC Cell Biol 9:50

    Article  PubMed Central  PubMed  Google Scholar 

  20. Meng XN, Jin Y, Yu Y, Bai J, Liu GY, Zhu J, Zhao YZ, Wang Z, Chen F, Lee KY, Fu SB (2009) Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion. Br J Cancer 101:327–334

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Ito Y, Kawakatsu H, Takeda T, Tani N, Kawaguchi N, Noguchi S, Sakai T, Matsuura N (2002) Activation of c-Src is inversely correlated with biological aggressiveness of breast carcinoma. Breast Cancer Res Treat 76:261–267

    Article  CAS  PubMed  Google Scholar 

  22. Rucci N, Recchia I, Angelucci A, Alamanou M, Del Fattore A, Fortunati D, Susa M, Fabbro D, Bologna M, Teti A (2006) Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: implications for therapy. J Pharmacol Exp Ther 318:161–172

    Article  CAS  PubMed  Google Scholar 

  23. Parsons JT (2003) Focal adhesion kinase: the first ten years. J Cell Sci 116:1409–1416

    Article  CAS  PubMed  Google Scholar 

  24. Shin NY, Dise RS, Schneider-Mergener J, Ritchie MD, Kilkenny DM, Hanks SK (2004) Subsets of the major tyrosine phosphorylation sites in Crk-associated substrate (CAS) are sufficient to promote cell migration. J Biol Chem 279:38331–38337

    Article  CAS  PubMed  Google Scholar 

  25. Brabek J, Constancio SS, Siesser PF, Shin NY, Pozzi A, Hanks SK (2005) Crk-associated substrate tyrosine phosphorylation sites are critical for invasion and metastasis of SRC-transformed cells. Mol Cancer Res 3:307–315

    Article  CAS  PubMed  Google Scholar 

  26. Brunton VG, Avizienyte E, Fincham VJ, Serrels B, Metcalf CA 3rd, Sawyer TK, Frame MC (2005) Identification of Src-specific phosphorylation site on focal adhesion kinase: dissection of the role of Src SH2 and catalytic functions and their consequences for tumor cell behavior. Cancer Res 65:1335–1342

    Article  CAS  PubMed  Google Scholar 

  27. Watermann DO, Gabriel B, Jager M, Orlowska-Volk M, Hasenburg A, zur Hausen A, Gitsch G, Stickeler E (2005) Specific induction of pp125 focal adhesion kinase in human breast cancer. Br J Cancer 93:694–698

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Defilippi P, Di Stefano P, Cabodi S (2006) p130Cas: a versatile scaffold in signaling networks. Trends Cell Biol 16:257–263

    Article  CAS  PubMed  Google Scholar 

  29. Vultur A, Buettner R, Kowolik C, Liang W, Smith D, Boschelli F, Jove R (2008) SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol Cancer Ther 7:1185–1194

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Chen PH, Peng CY, Pai HC, Teng CM, Chen CC, Yang CR (2011) Denbinobin suppresses breast cancer metastasis through the inhibition of Src-mediated signaling pathways. J Nutr Biochem 22:732–740

    Article  CAS  PubMed  Google Scholar 

  31. McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC (2005) The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer 5:505–515

    Article  CAS  PubMed  Google Scholar 

  32. Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R, Mirosevich J, Lee FY, Jove R (2005) Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res 65:9185–9189

    Article  CAS  PubMed  Google Scholar 

  33. Schaller MD (2001) Paxillin: a focal adhesion-associated adaptor protein. Oncogene 20:6459–6472

    Article  CAS  PubMed  Google Scholar 

  34. Sachdev S, Bu Y, Gelman IH (2009) Paxillin-Y118 phosphorylation contributes to the control of Src-induced anchorage-independent growth by FAK and adhesion. BMC Cancer 9:12

    Article  PubMed Central  PubMed  Google Scholar 

  35. Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25:9–34

    Article  CAS  PubMed  Google Scholar 

  36. Buettner R, Mesa T, Vultur A, Lee F, Jove R (2008) Inhibition of Src family kinases with dasatinib blocks migration and invasion of human melanoma cells. Mol Cancer Res 6:1766–1774

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Pan X, Han H, Wang L, Yang L, Li R, Li Z, Liu J, Zhao Q, Qian M, Liu M, Du B (2011) Nitidine chloride inhibits breast cancer cells migration and invasion by suppressing c-Src/FAK associated signaling pathway. Cancer Lett 313:181–191

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Grants from the National Science Council of Taiwan (NSC97-2320-B-037-008-MY3) and NSYSU-KMU Joint Research Project (NSYSUKMU-102-004).

Conflict of interest

No conflicts of interest were stated.

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Authors and Affiliations

  1. Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Pei-Chien Tsai, Chiao-Lun Chu, Yeh-long Chen & Shinne-Ren Lin

  2. Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Yaw-Syan Fu

  3. School of Pharmacy, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Chih-Hua Tseng

  4. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan

    Long-Sen Chang

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  1. Pei-Chien Tsai
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  4. Chih-Hua Tseng
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Correspondence to Shinne-Ren Lin.

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Tsai, PC., Chu, CL., Fu, YS. et al. Naphtho[1,2-b]furan-4,5-dione inhibits MDA-MB-231 cell migration and invasion by suppressing Src-mediated signaling pathways. Mol Cell Biochem 387, 101–111 (2014). https://doi.org/10.1007/s11010-013-1875-4

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  • DOI: https://doi.org/10.1007/s11010-013-1875-4

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