In this study, the roles of matrix metalloproteinase (MMP)-2 and MMP-9 in platelet-activating factor (PAF)-induced experimental pulmonary metastasis of the murine melanoma cell, B16F10, were investigated. An injection of PAF resulted in increases in mRNA expression, protein levels and the activities of both MMP-2 and MMP-9 in the lungs. The overall expression of MMP-9 was stronger than that of MMP-2. The increased MMP-9 expression was inhibited by both NF-jB and AP-1 inhibitors, whereas the increased MMP-2 expression was inhibited by only AP-1 inhibitors. Immunohistochemical analysis revealed that MMP-9 was expressed in bronchial epithelial cells as well as in the walls of blood vessels, whereas MMP-2 expression was observed only in bronchial epithelial cells. PAF significantly enhanced the pulmonary metastasis of B16F10, which was inhibited by both NF-jB and c-jun inhibitors. MMP-9 inhibitor, but not that of MMP-2, completely inhibited PAF-induced B16F10 metastasis. These data indicate that MMP-9, the expression of which was regulated by NF-jB and AP-1, plays a critical role in PAF-induced enhancement of pulmonary melanoma metastasis. ' 2006 Wiley-Liss, Inc.
Ginkgetin has been reported to display antitumor activity. However, the relevant pathway integrating cell cycle regulation and signaling pathways involved in growth inhibition in CRC cells remains to be identified. In this study, ginkgetin-treated HCT116 CRC cells exhibited significant dose-dependent growth inhibition with a GI50 value of 4.0 µM for 48-h treatment, together with apoptosis, via G2-phase cell cycle arrest. When HCT116 cells were treated with 10 µM ginkgetin for 48 h, the percentage of cells in G2/M phase increased by 2.2-fold (43.25%) versus the untreated control (19.69%). Ginkgetin regulated the expression of genes that are critically involved in G2 phase arrest cells, such as b‑Myb, CDC2 and cyclin B1. Furthermore, we found that the suppression of b‑Myb expression by ginkgetin was rescued ~5.1-fold by treatment with a miR-34a inhibitor (500 nM) and b‑Myb was downregulated by >80% by 100 nM miR‑34a mimic. These data suggest that the miRNA34a/b‑Myb/cyclin B1 cascade plays a critical role in ginkgetin-induced G2 cell cycle arrest, as well as in the inhibition of HCT116 cell proliferation. Moreover, the administration of ginkgetin (10 mg/kg) reduced tumor volumes by 36.5% and tumor weight by 37.6% in the mice xenografted with HCT116 cells relative to their vehicle-treated counterparts. Therefore, ginkgetin is the first compound shown to regulate b‑Myb by modulating miR-34a, and we suggest the use of ginkgetin as an inducer of G2 arrest for the treatment of CRC.
We investigated the role of p53 in nuclear factor (NF)-jB dependent, platelet-activating factor (PAF)-induced vascular endothelial growth factor (VEGF) expression. Transfected NF-jB subunits in ECV304 cells increased the tumor necrosis factor-a promoter activity, which was completely inhibited by p53. Transfected p53 increased p53RE promoter activity, which was completely inhibited by NF-jB subunits, indicating that cross-regulation occurs between NF-jB and p53. PAFinduced increase in VEGF expression was correlated with decreased p53 activity. These data suggest that NF-jB-dependency of the PAF-induced increase in VEGF expression is due to decreased p53 activity, which is reciprocally regulated by increased NF-jB activity.
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