Malignant tumors have a capability to degrade the extracellular matrix (ECM) by controlled proteolysis. One of the important components of the proteolytic system involved in such processes is urokinase-type plasminogen activator (uPA). Tumor necrosis factor (TNF)-α was found to stimulate uPA. TNF-α impaired the ability of cells to aggregate and to attain compaction. Dyscohesion (cell-cell dissociation) induced by TNF-α was associated with the disordered expression of cadherin/beta-catenin at the sites of cell-cell contact. Since TNF-α plays a crucial role in the regulation of uPA expression, the development of molecules capable of modulating TNF-α-induced signaling is an issue of concern. We observed that human breast epithelial (MCF-10A) cells treated with TNF-α transiently up-regulated uPA mRNA and protein expression. In addition, TNF-α induced expression as well as nuclear translocation of β-catenin in MCF-10A cells. Based on these findings, we attempted to examine the role of β-catenin and its partner, TCF-4 in upregulation of uPA. When MCF-10A cells were transfected with β-catenin siRNA, TNF-α-induced TCF-4 DNA binding activity and uPA expression were attenuated. TNF-α-stimulated MCF-10A cells exhibited increased intracellular accumulation of reactive oxygen species (ROS). TNF-α-induced expression of β-catenin and uPA appear to be mediated by ROS in MCF-10A cells, as both events were blocked by the antioxidant N-acetylcysteine (NAC). One of the plausible ways to prevent the ROS-mediated cellular injury is dietary or pharmaceutical augmentation of endogenous antioxidant defense capacity. Euaptilin (5,7-dihydroxy-3,4,6-tri-methoxy-flavone), a pharmacologically active flavone derived from Artemisia asiatica, has been shown to possess strong antioxidative activity. Eupatilin inhibited TNF-α-induced uPA expression of beta-catenin and TCF-4 DNA binding activity. Moreover, eupatilin inhibited the TNF-α-induced invasion of MCF-10A cells. Taken together, the above results suggest that eupatilin has chemotherapeutic potential by targeting TNF-α-mediated tumor invasion and metastasis.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]