Berberine Reverses Epithelial-to-Mesenchymal Transition and Inhibits Metastasis and Tumor-Induced Angiogenesis in Human Cervical Cancer Cells

• DOI: 10.1124/mol.114.094037
• Publication Date: 2014-12-01
• Authors: Kuo-Shuen Chen; Cheng-Chia Yu; Pei-Ni Chen; Shu-Chen Chu; Li-Sung Hsu; Mei-Yu Su
• Keywords: 0303 health sciences; Epithelial-Mesenchymal Transition; Berberine; Neovascularization, Pathologic; Uterine Cervical Neoplasms; Urokinase-Type Plasminogen Activator; Chorioallantoic Membrane; 3. Good health; Transforming Growth Factor beta1; Mice; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Animals; Humans; Matrix Metalloproteinase 2; Female; Neoplasm Metastasis; Chickens; Zebrafish; beta Catenin

Metastasis is the most common cause of cancer-related death in patients, and epithelial-to-mesenchymal transition (EMT) is essential for cancer metastasis, which is a multistep complicated process that includes local invasion, intravasation, extravasation, and proliferation at distant sites. When cancer cells metastasize, angiogenesis is also required for metastatic dissemination, given that an increase in vascular density will allow easier access of tumor cells to circulation, and represents a rational target for therapeutic intervention. Berberine has several anti-inflammation and anticancer biologic effects. In this study, we provided molecular evidence that is associated with the antimetastatic effect of berberine by showing a nearly complete inhibition on invasion (P < 0.001) of highly metastatic SiHa cells via reduced transcriptional activities of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Berberine reversed transforming growth factor-β1-induced EMT and caused upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and snail-1. Selective snail-1 inhibition by snail-1-specific small interfering RNA also showed increased E-cadherin expression in SiHa cells. Berberine also reduced tumor-induced angiogenesis in vitro and in vivo. Importantly, an in vivo BALB/c nude mice xenograft model and tail vein injection model showed that berberine treatment reduced tumor growth and lung metastasis by oral gavage, respectively. Taken together, these findings suggested that berberine could reduce metastasis and angiogenesis of cervical cancer cells, thereby constituting an adjuvant treatment of metastasis control.