Advertisement

Chinese Journal of Integrative Medicine

, Volume 23, Issue 2, pp 110–116 | Cite as

Brucine inhibits bone metastasis of breast cancer cells by suppressing Jagged1/Notch1 signaling pathways

  • Ke-fei Hu
  • Xiang-ying Kong
  • Mi-cun Zhong
  • Hong-ye Wan
  • Na Lin
  • Xiao-hua Pei
Original Article

Abstract

Objective

To examine the effects of brucine on the invasion, migration and bone resorption of receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis.

Methods

The osteoclastogenesis model was builded by co-culturing human breast tumor MDA-MB-231 and mouse RAW264.7 macrophages cells. RANKL (50 ng/mL) and macrophage-colony stimulating factor (50 ng/mL) were added to this system, followed by treatment with brucine (0.02, 0.04 and 0.08 mmol/L), or 10 μmol/L zoledronic acid as positive control. The migration and bone resorption were measured by transwell assay and in vitro bone resorption assay. The protein expressions of Jagged1 and Notch1 were investigated by Western blot. The expressions of transforming growth factor-β1 (TGF-β1), nuclear factor-kappa B (NF-κB) and Hes1 were determined by enzyme-linked immunosorbent assay.

Results

Compared with the model group, brucine led to a dose-dependent decrease on migration of MDA-MB-231 cells, inhibited RANKL-induced osteoclastogenesis and bone resorption of RAW264.7 cells (P<0.01). Furthermore, brucine decreased the protein levels of Jagged1 and Notch1 in MDA-MB-231 cells and RAW264.7 cells co-cultured system as well as the expressions of TGF-β1, NF-κB and Hes1 (P<0.05 or P<0.01).

Conclusion

Brucine may inhibit osteoclastogenesis by suppressing Jagged1/Notch1 signaling pathways.

Keywords

brucine breast cancer bone metastasis Jagged1/Notch1 signaling pathway 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Zhang Y, Ma B, Fan Q. Mechanisms of breast cancer bone metastasis. Cancer Lett 2010;292:1–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584–593.CrossRefPubMedGoogle Scholar
  3. 3.
    Mundy GR. Mechanisms of bone metastasis. Cancer 1997;80:1546–1556.CrossRefPubMedGoogle Scholar
  4. 4.
    Clezardin P. Therapeutic targets for bone metastases in breast cancer. Breast Cancer Res 2011;13:207.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hofbauer LC, Kuhne CA, Viereck V. The OPG/RANKL/RANK system in metabolic bone diseases. J Musculoskelet Neuronal Interact 2004;4:268–275.PubMedGoogle Scholar
  6. 6.
    Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003;3:537–549.CrossRefPubMedGoogle Scholar
  7. 7.
    Fukushima H. Regulatory mechanisms of Notch signaling in osteoclast differentiation. J Oral Biosciences 2010;52:205–214.CrossRefGoogle Scholar
  8. 8.
    Chiechi A, Waning DL, Stayrook KR, Buijs JT, Guise TA, Mohammad KS. Role of TGF-ß in breast cancer bone metastases. Adv Biosci Biotechnol 2013;4:15–30.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Park BK, Zhang H, Zeng Q, Dai J, Keller ET, Giordano T, et al. NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GMCSF. Nat Med 2007;13:62–69.CrossRefPubMedGoogle Scholar
  10. 10.
    Kuramoto T, Goto H, Mitsuhashi A, Tabata S, Ogawa H, Uehara H, et al. Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through the downregulation of the NF-kappaB activity. Mol Cancer Ther 2012;11:2578–2587.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang W, Grivennikov SI. Top Notch cancer stem cells by paracrine NF-kappaB signaling in breast cancer. Breast Cancer Res 2013;15:316.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Sethi N, Dai X, Winter CG, Kang Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 2011;19:192–205.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Sethi N, Kang Y. Notch signalling in cancer progression and bone metastasis. Br J Cancer 2011;105:1805–1810.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhang P, Yang Y, Zweidler-McKay PA, Hughes DP. Critical role of notch signaling in osteosarcoma invasion and metastasis. Clin Cancer Res 2008;14:2962–2969.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhao LM, Liu YG, Niu ZX. Anti-tumor effect on brucine. Chin J Cancer Treat (Chin) 2013;20:877–880.Google Scholar
  16. 16.
    Serasanambati M, Chilakapati SR, Manikonda PK, Kanala JR, Chilakapati DR. Anticancer effects of brucine and gemcitabine combination in MCF-7 human breast cancer cells. Nat Prod Res 2015;29:484–490.CrossRefPubMedGoogle Scholar
  17. 17.
    Agrawal SS, Saraswati S, Mathur R, Pandey M. Cytotoxic and antitumor effects of brucine on Ehrlich ascites tumor and human cancer cell line. Life Sci 2011;89:147–158.CrossRefPubMedGoogle Scholar
  18. 18.
    Deng XK, Yin W, Li WD, Yin FZ, Lu XY, Zhang XC, et al. The anti-tumor effects of alkaloids from the seeds of Strychnos nux-vomica on HepG2 cells and its possible mechanism. J Ethnopharmacol 2006;106:179–186.CrossRefPubMedGoogle Scholar
  19. 19.
    Deng X, Yin F, Lu X, Cai B, Yin W. The apoptotic effect of brucine from the seed of Strychnos nux-vomica on human hepatoma cells is mediated via Bcl-2 and Ca2+ involved mitochondrial pathway. Toxicol Sci 2006;91:59–69.CrossRefPubMedGoogle Scholar
  20. 20.
    Ma WJ, Li P. Effects of brucine on breast cancer bone metastasis in mice. Anhui Med Pharm (Chin) 2009;13:600–602.Google Scholar
  21. 21.
    Li P, Zhang M, Ma WJ, Sun X, Jin FP. Effects of brucine on vascular endothelial growth factor expression and microvessel density in a nude mouse model of bone metastasis due to breast cancer. Chin J Integr Med 2012;18:605–609.CrossRefPubMedGoogle Scholar
  22. 22.
    Lowery FJ, Yu D. Growth factor signaling in metastasis: current understanding and future opportunities. Cancer Metastasis Rev 2012;31:479–491.CrossRefPubMedGoogle Scholar
  23. 23.
    Schneider D, Liaw L, Daniel C, Athanasopoulos AN, Herrmann M, Preissner KT, et al. Inhibition of breast cancer cell adhesion and bone metastasis by the extracellular adherence protein of Staphylococcus aureus. Biochem Biophys Res Commun 2007;357:282–288.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Dempster DW, Moonga BS, Stein LS, Horbert WR, Antakly T. Glucocorticoids inhibit bone resorption by isolated rat osteoclasts by enhancing apoptosis. J Endocrinol 1997;154:397–406.CrossRefPubMedGoogle Scholar
  25. 25.
    Bai S, Kopan R, Zou W, Hilton MJ, Ong CT, Long F, et al. NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem 2008;283:6509–6518.CrossRefPubMedGoogle Scholar
  26. 26.
    Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S. Interleukin-1beta and tumor necrosis factoralpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 1999;25:255–259.CrossRefPubMedGoogle Scholar
  27. 27.
    Cao L, Arany PR, Wang YS, Mooney DJ. Promoting angiogenesis via manipulation of VEGF responsiveness with notch signaling. Biomaterials 2009;30:4085–4093.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 2006;24:99–146.CrossRefPubMedGoogle Scholar

Copyright information

© Chinese Association of the Integration of Traditional and Western Medicine and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ke-fei Hu
    • 1
  • Xiang-ying Kong
    • 2
  • Mi-cun Zhong
    • 2
  • Hong-ye Wan
    • 2
  • Na Lin
    • 2
  • Xiao-hua Pei
    • 3
  1. 1.Beijing University of Chinese MedicineBeijingChina
  2. 2.Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijingChina
  3. 3.Department of Scientific Research and EducationBeijing University of Chinese Medicine Third Affiliated HospitalBeijingChina

Personalised recommendations