Sesamin inhibits macrophage-induced vascular endothelial growth factor and matrix metalloproteinase-9 expression and proangiogenic activity in breast cancer cells.
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.
Lee
Chun-Chung
CC
National Institute of Cancer Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County, 350, Taiwan, Republic of China.
Liu
Ko-Jiunn
KJ
Wu
Yu-Chen
YC
Lin
Sue-Jane
SJ
Chang
Ching-Chun
CC
Huang
Tze-Sing
TS
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D004149:Dioxoles / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000235:genetics; D017705:Lignans / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000093242:Interleukin-6 Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D017077:Culture Media, Conditioned; D004149:Dioxoles; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D016209:Interleukin-8; D017705:Lignans; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C508606:CXCL8 protein, human; C497442:HIF1A protein, human; C508600:IL6 protein, human; C467484:VEGFA protein, human; C054125:sesamin