Sesamin Inhibits Macrophage-Induced Vascular Endothelial Growth Factor and Matrix Metalloproteinase-9 Expression and Proangiogenic Activity in Breast Cancer Cells

Abstract

Sesamin is a sesame component with antihypertensive and antioxidative activities and has recently aroused much interest in studying its potential anticancer application. Macrophage is one of the infiltrating inflammatory cells in solid tumor and may promote tumor progression via enhancement of tumor angiogenesis. In this study, we investigated whether sesamin inhibited macrophage-enhanced proangiogenic activity of breast cancer cell lines MCF-7 and MDA-MB-231. Using vascular endothelial cell capillary tube and network formation assays, both breast cancer cell lines exhibited elevated proangiogenic activities after coculture with macrophages or pretreatment with macrophage-conditioned medium. This elevation of proangiogenic activity was drastically suppressed by sesamin. Vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) induced by macrophages in both cell lines were also inhibited by sesamin. Nuclear levels of HIF-1α and NF-κB, important transcription factors for VEGF and MMP-9 expression, respectively, were obviously reduced by sesamin. VEGF induction by macrophage in MCF-7 cells was shown to be via ERK, JNK, phosphatidylinositol 3-kinase, and NF-κB-mediated pathways. These signaling molecules and additional p38(MAPK) were also involved in macrophage-induced MMP-9 expression. Despite such diverse pathways were induced by macrophage, only Akt and p38(MAPK) activities were potently inhibited by sesamin. Expression of interleukin (IL)-6, IL-8, and tumor necrosis factor-α were substantially increased and involved in macrophage-induced VEGF and MMP-9 mRNA expression in MCF-7 cells. Sesamin effectively inhibited the expression of these cytokines to avoid the reinforced induction of VEGF and MMP-9. In conclusion, sesamin potently inhibited macrophage-enhanced proangiogenic activity of breast cancer cells via inhibition of VEGF and MMP-9 induction.

Chemokine Signaling and the Regulation of Bidirectional Leukocyte Migration in Interstitial Tissues

“…Previously published findings implicate a role for macrophage-produced ROS signaling in driving neutrophil reverse migration from the wound (Tauzin et al, 2014). Additionally, our current findings suggest that macrophages or other cells in the wound microenvironment may produce factors such as Cxcl8 that drive neutrophil reverse migration (Figure 7F)(Lee et al, 2011; Park et al, 2003). Importantly, we found that macrophages at the wound are not sufficient to drive neutrophil reverse migration in the absence of Cxcl8a/Cxcr2, suggesting that macrophage-mediated neutrophil resolution requires Cxcl8 signaling.…”

Differentiation therapy: sesamin as an effective agent in targeting cancer stem-like side population cells of human gallbladder carcinoma

“…Aki et al [13] and Lee et al [37] reported that sesamin decreases the protein expression of NF-κB in breast cancer. Harikumar et al [12] demonstrated that sesamin down-regulates constitutive and inducible NF-κB activation and expression in human chronic myeloid leukemia cell lines.…”

Natural Polyphenols for Prevention and Treatment of Cancer

“…Sesamin treatment (1, 10 and 50 μM) dose-dependently decreased cell viability and increased apoptosis in MCF-7 breast cancer cells. The lignan (10–100 μM) also inhibited the pro-angiogenic activity of macrophages in MCF-7 cells by down-regulating VEGF and MMP-9 [162]. Besides, it was suggested that STAT3 played an important role in sesamin (25–125 μM) induced G 2 /M cell cycle arrest and apoptosis in HepG2 cells [163].…”