Cucurbitacin B inhibits breast cancer metastasis and angiogenesis through VEGF-mediated suppression of FAK/MMP-9 signaling axis. (August 2016)

• Record Type: Journal Article
• Authors: Sinha, Sonam; Khan, Sajid; Shukla, Samriddhi; Lakra, Amar Deep; Kumar, Sudhir; Das, Gunjan; Maurya, Rakesh; Meeran, Syed Musthapa
• Is Part Of: International journal of biochemistry & cell biology. Volume 77:Part A(2016:Aug.)
• Page Start: 41
• Page End: 56
• Publication Date: 2016-08
• Subjects: bFGF basic fibroblast growth factor -- CuB Cucurbitacin B -- CAM chorioallantoic membrane -- ECM extracellular matrix -- FAK focal adhesion kinase -- HUVECs human umbilical vein endothelial cells -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- VEGF vascular endothelial growth factor; Cucurbitacin B -- Breast cancer -- Metastasis -- Cancer prevention -- Invasion -- Angiogenesis; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2016.05.014
• Languages: English
• ISSNs: 1357-2725

Abstract

Highlights: Cucurbitacin B (CuB) exhibits anti-proliferative and pro-apoptotic effects in breast cancer cells. CuB inhibits migration and invasion potential of highly metastatic breast cancer cells. CuB-inhibits both in vitro and ex vivo angiogenesis. CuB-inhibits metastasis and angiogenesis through downregulation of VEGF/FAK/MMP-signaling. CuB inhibits mammary tumor growth, lung metastasis and angiogenesis in vivo . Abstract: Available breast cancer therapeutic strategies largely target the primary tumor but are ineffective against tumor metastasis and angiogenesis. In our current study, we determined the effect of Cucurbitacin B (CuB), a plant triterpenoid, on the metastatic and angiogenic potential of breast cancer cells. CuB was found to inhibit cellular proliferation and induce apoptosis in breast cancer cells in a time- and dose-dependent manner. Further, CuB-treatment significantly inhibited the migratory and invasive potential of highly metastatic breast cancer MDA-MB-231 and 4T1 cells at sub-IC50 concentrations, where no significant apoptosis was observed. CuB was also found to inhibit migratory, invasive and tube-forming capacities of HUVECs in vitro . In addition, inhibition of pre-existing vasculature in chick embryo chorioallantoic membrane ex vivo further supports the anti-angiogenic effect of CuB. CuB-mediated anti-metastatic and anti-angiogenic effects were associated with the downregulation of VEGF/FAK/MMP-9 signaling, which has been validated by using FAK-inhibitor (FI-14). CuB-treatment resulted in a significant inhibition of VEGF-induced phosphorylation of FAK and MMP-9 expressions similar to the action of FI-14. CuB was also found to decrease the micro-vessel density as evidenced by the decreased expression of CD31, a marker for neovasculature. Further, CuB-treatment inhibited tumor growth, lung metastasis and angiogenesis in a highly metastatic 4T1-syngeneic mouse mammary cancer. Collectively, our findings suggest that CuB inhibited breast cancer metastasis and angiogenesis, at least in part, through the downregulation of VEGF/FAK/MMP-9 signaling.