Kahweol의 염증 및 암 전이 조절 연구

Abstract

The coffee diterpene kahweol inhibits tumor necrosis factor-？\-induced expression of cell adhesion molecules in human endothelial cells: Endothelial cells produce adhesion molecules after being stimulated with various inflammatory cytokines. These adhesion molecules play an important role in the development of atherogenesis. Recent studies have highlighted the chemoprotective and anti-inflammatory effects of kahweol, a coffee-specific diterpene. This study examined the effects of kahweol on the cytokine-induced monocyte/human endothelial cell interaction, which is a crucial early event in atherogenesis. Kahweol inhibited the adhesion of TNF？\-induced monocytes to endothelial cells and suppressed the TNF？\-induced protein and mRNA expression of the cell adhesion molecules, VCAM-1 and ICAM-1. Furthermore, kahweol inhibited the TNF？\-induced JAK2-PI3K/Akt-NF-？eB activation pathway in these cells. Overall, kahweol has anti-inflammatory and anti-atherosclerotic activities, which occurs partly by down-regulating the pathway that affects the expression and interaction of the cell adhesion molecules on endothelial cells. Kahweol blocks STAT3 phosphorylation and induces apoptosis in human lung adenocarcinoma A549 cells: Kahweol, the coffee-specific diterpene, has been reported to have anti-carcinogenic properties. Animal data support such a chemopreventive effect of coffee. However, the precise underlying protective mechanisms are poorly understood. In this study, the apoptotic effect of kahweol in human lung adenocarcinoma A549 cells was investigated. In cell viability assays and cell proliferation assays, kahweol exhibited anti-proliferative and pro-apoptotic effects on A549 cells in a time- and dose-dependent manner. Kahweol considerably inhibited the expression of Bcl-2 but increased that of Bax; it also stimulated the cleavage of caspase-3 and PARP (poly ADP-ribose polymerase). In addition, kahweol-induced apoptosis was confirmed by TUNEL assays. Furthermore, kahweol inhibited dose-dependent phosphorylation of signal transducer and activator of transcription 3 (STAT3). An overexpression in STAT3 led to resistance to kahweol-induced apoptosis, suggesting that STAT3 was a critical target of kahweol. These findings suggest that kahweol inhibited A549 cell growth and induced apoptosis via down-regulation of STAT3 signaling pathway. Kahweol inhibit angiogenesis and metastasis through suppression of STAT3 activation: Kahweol, a coffee-specific diterpene, is reported to have anti-cancer properties, although its precise chemopreventive mechanism remains unclear. In this study, the antiangiogenic and anti-metastatic activities of kahweol was investigated. Kahweol effectively inhibited interleukin-6-induced production of vascular endothelial growth factor (VEGF), as well as the migration and tube formation of human umbilical vein endothelial cells. Kahweol also inhibited cell migration, VEGF production, and matrix metalloproteinase (MMP)-2 and -9 activities in the MDA-MB231 breast cancer cell line. Moreover, kahweol inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), suggesting that STAT3？Vresponsive regions in the VEGF and MMP promoters may underlie the inhibitory effects of kahweol. The transient expression of constitutively active STAT3 significantly reduced the inhibitory effects of kahweol on cell migration, invasion, and VEGF expression. Collectively, these data suggest that kahweol inhibits metastasis and angiogenesis, at least in part, through the disruption of STAT3-mediated transcription of the MMP and VEGF genes.