Moscatilin inhibits migration and metastasis of human breast cancer MDA-MB-231 cells through inhibition of Akt and Twist signaling pathway
- 1.1k Downloads
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.
KeywordsMoscatilin 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).
- 3.Iwata H (2011) Future treatment strategies for metastatic breast cancer: curable or incurable? Breast Cancer 19:200-205Google Scholar
- 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
- 13.Tomaskovic-Crook E, Thompson EW, Thiery JP (2009) Epithelial to mesenchymal transition and breast cancer. Breast Cancer Res 11, Artn 213Google Scholar
- 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.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
- 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