Journal of Molecular Medicine

, Volume 91, Issue 3, pp 347–356 | Cite as

Moscatilin inhibits migration and metastasis of human breast cancer MDA-MB-231 cells through inhibition of Akt and Twist signaling pathway

  • Hui-Chen Pai
  • Li-Hsun Chang
  • Chieh-Yu Peng
  • Ya-Ling Chang
  • Chien-Chih Chen
  • Chien-Chang Shen
  • Che-Ming TengEmail author
  • Shiow-Lin PanEmail author
Original Article


Breast cancer metastasis is more resistant to chemotherapy and radiotherapy than is cancer of the visceral tissues; therefore, new treatment strategies are urgently needed. Moscatilin, derived from the orchid Dendrobrium loddigesii, has shown anticancer activity. We evaluated the mechanism by which moscatilin suppresses the migration and metastasis of human breast cancer MDA-MB-231 cells in vitro and in vivo. We demonstrated that moscatilin significantly inhibits MDA-MB-231 cell migration by using scratch assays and Boyden chambers. Transcriptional factors inducing epithelial–mesenchymal transition, such as Twist, Snail, and Akt, play important roles in cell migration and cancer metastasis. Moscatilin inhibited the mRNA and protein expression of Twist, but not that of Snail, and subsequently inhibited N-cadherin expression. However, these effects were reversed by constitutively expressing active myristoylated (myr)-Akt and Twist overexpression. Moscatilin also suppressed Akt phosphorylation. However, Akt overexpression reversed the inhibitory effects of moscatilin on phospho-Akt protein expression but not its effects on Twist. The moscatilin-mediated inhibition of cell migration was reversed by Akt and Twist overexpression, demonstrating that moscatilin blocked cell migration by inhibiting Akt and Twist. In an MDA-MB-231 metastatic animal model, moscatilin (100 mg/kg) significantly suppressed breast cancer metastasis to the lungs and reduced the number of metastatic lung nodules and lung weight without causing any toxicity. These results indicated that moscatilin inhibited MDA-MB-231 cell migration via Akt- and Twist-dependent pathways; this finding was consistent with moscatilin’s antimetastatic activity in vivo. Therefore, moscatilin may be an effective compound for the prevention of human breast cancer metastasis.


Moscatilin Breast cancer Migration Twist 



This study was supported by grants from the National Science Council of Taiwan (NSC 99-2320-B400-008-MY3) and (NSC 99-2628-B002-024-MY3).

Supplementary material

109_2012_945_MOESM1_ESM.pdf (236 kb)
ESM 1 (PDF 235 kb)


  1. 1.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300PubMedCrossRefGoogle Scholar
  2. 2.
    Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, Nielsen TO, Gelmon K (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28:3271–3277PubMedCrossRefGoogle Scholar
  3. 3.
    Iwata H (2011) Future treatment strategies for metastatic breast cancer: curable or incurable? Breast Cancer 19:200-205Google Scholar
  4. 4.
    Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–939PubMedCrossRefGoogle Scholar
  5. 5.
    Wang X, Ling MT, Guan XY, Tsao SW, Cheung HW, Lee DT, Wong YC (2004) Identification of a novel function of TWIST, a bHLH protein, in the development of acquired taxol resistance in human cancer cells. Oncogene 23:474–482PubMedCrossRefGoogle Scholar
  6. 6.
    Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428PubMedCrossRefGoogle Scholar
  7. 7.
    Parker BS, Argani P, Cook BP, Liangfeng H, Chartrand SD, Zhang M, Saha S, Bardelli A, Jiang Y, St Martin TB et al (2004) Alterations in vascular gene expression in invasive breast carcinoma. Cancer Res 64:7857–7866PubMedCrossRefGoogle Scholar
  8. 8.
    Chen TH, Pan SL, Guh JH, Liao CH, Huang DY, Chen CC, Teng CM (2008) Moscatilin induces apoptosis in human colorectal cancer cells: a crucial role of c-Jun NH2-terminal protein kinase activation caused by tubulin depolymerization and DNA damage. Clin Cancer Res 14:4250–4258PubMedCrossRefGoogle Scholar
  9. 9.
    Liu YN, Pan SL, Peng CY, Huang DY, Guh JH, Chen CC, Shen CC, Teng CM (2010) Moscatilin repressed lipopolysaccharide-induced HIF-1alpha accumulation and NF–kappaB activation in murine RAW264.7 cells. Shock 33:70–75PubMedCrossRefGoogle Scholar
  10. 10.
    Tsai AC, Pan SL, Liao CH, Guh JH, Wang SW, Sun HL, Liu YN, Chen CC, Shen CC, Chang YL et al (2010) Moscatilin, a bibenzyl derivative from the India orchid Dendrobrium loddigesii, suppresses tumor angiogenesis and growth in vitro and in vivo. Cancer Lett 292:163–170PubMedCrossRefGoogle Scholar
  11. 11.
    Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ (2008) Direct regulation of TWIST by HIF-1 alpha promotes metastasis. Nat Cell Biol 10:295–305PubMedCrossRefGoogle Scholar
  12. 12.
    Thiery JP, Acloque H, Huang RYJ, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890PubMedCrossRefGoogle Scholar
  13. 13.
    Tomaskovic-Crook E, Thompson EW, Thiery JP (2009) Epithelial to mesenchymal transition and breast cancer. Breast Cancer Res 11, Artn 213Google Scholar
  14. 14.
    Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829PubMedCrossRefGoogle Scholar
  15. 15.
    Montserrat N, Gallardo A, Escuin D, Catasus L, Prat J, Gutierrez-Avigno FJ, Peiro G, Barnadas A, Lerma E (2011) Repression of E-cadherin by SNAIL, ZEB1, and TWIST in invasive ductal carcinomas of the breast: a cooperative effort? Hum Pathol 42:103–110PubMedCrossRefGoogle Scholar
  16. 16.
    Nguyen DX, Massague J (2007) Genetic determinants of cancer metastasis. Nat Rev Genet 8:341–352PubMedCrossRefGoogle Scholar
  17. 17.
    Li J, Zhou BP (2011) Activation of beta-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer 11:49PubMedCrossRefGoogle Scholar
  18. 18.
    Li JL, Zhou BHP (2011) Activation of beta-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer 11:49Google Scholar
  19. 19.
    Evdokimova V, Tognon C, Ng T, Ruzanov P, Melnyk N, Fink D, Sorokin A, Ovchinnikov LP, Davicioni E, Triche TJ et al (2009) Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition. Cancer Cell 15:402–415PubMedCrossRefGoogle Scholar
  20. 20.
    Yu L, Li HZ, Lu SM, Tian JJ, Ma JK, Wang HB, Xu W (2011) Down-regulation of TWIST decreases migration and invasion of laryngeal carcinoma Hep-2 cells by regulating the E-cadherin, N-cadherin expression. J Cancer Res Clin 137:1487–1493CrossRefGoogle Scholar
  21. 21.
    Cheng GZ, Chan J, Wang Q, Zhang WZ, Sun CD, Wang LH (2007) Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res 67:1979–1987PubMedCrossRefGoogle Scholar
  22. 22.
    Qiao M, Sheng SJ, Pardee AB (2008) Metastasis and AKT activation. Cell Cycle 7:2991–2996PubMedCrossRefGoogle Scholar
  23. 23.
    Vichalkovski A, Gresko E, Hess D, Restuccia DF, Hemmings BA (2010) PKB/AKT phosphorylation of the transcription factor Twist-1 at Ser42 inhibits p53 activity in response to DNA damage. Oncogene 29:3554–3565PubMedCrossRefGoogle Scholar
  24. 24.
    Pham CG, Bubici C, Zazzeroni F, Knabb JR, Papa S, Kuntzen C, Franzoso G (2007) Upregulation of Twist-1 by NF–kappaB blocks cytotoxicity induced by chemotherapeutic drugs. Mol Cell Biol 27:3920–3935PubMedCrossRefGoogle Scholar
  25. 25.
    Montagut C, Tusquets I, Domingo-Domenech J, Corominas JM, Ferrer B, Bellosillo B, Fernandez PL, Rovira A, Suarez M (2005) Activation of nuclear factor (NF)–kB is linked to resistance to neoadjuvant chemotherapy in breast cancer patients. Breast Cancer Res Tr 94:S160–S161Google Scholar
  26. 26.
    Li Q, Liu BC, Lv LL, Ma KL, Zhang XL, Phillips AO (2011) Monocytes induce proximal tubular epithelial-mesenchymal transition through NF–kappa B dependent upregulation of ICAM-1. J Cell Biochem 112:1585–1592PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Hui-Chen Pai
    • 1
  • Li-Hsun Chang
    • 1
  • Chieh-Yu Peng
    • 2
    • 3
  • Ya-Ling Chang
    • 1
  • Chien-Chih Chen
    • 4
  • Chien-Chang Shen
    • 5
  • Che-Ming Teng
    • 1
    Email author
  • Shiow-Lin Pan
    • 6
    • 7
    Email author
  1. 1.Phamacological Institute, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  2. 2.Natural Medicinal Products Research CenterChina Medical University HospitalTaichungTaiwan
  3. 3.School of Chinese MedicineChina Medical UniversityTaichungTaiwan
  4. 4.Department of BiotechnologyHungkuang UniversityTaichungTaiwan
  5. 5.National Research Institute of Chinese MedicineTaipeiTaiwan
  6. 6.Institute of Biotechnology and Pharmaceutical ResearchNational Health Research InstitutesZhunanTaiwan
  7. 7.Department of PharmacologyTaipei Medical UniversityTaipeiTaiwan

Personalised recommendations