Overexpression of tissue inhibitors of metalloproteinase 2 up-regulates NF-kappaB activity in melanoma cells.

Abstract

Background: Matrix Metalloproteinase functions in the remodeling of the extracellular matrix that is integral for many normal and pathological processes such as morphogenesis, angiogenesis, tissue repair, and tumor invasion. The tissue inhibitor of the metalloproteinase family including the tissue inhibitor of metalloproteinase-2 (TIMP-2) regulates the activity of multifunctional metalloproteinase. It is known that IL-8, the target gene of NF-kappaB pathway, increases in the melanoma cells. However, it is not clear whether the TIMP-2 expression regulates the NF-kappaB pathway. In this study, we have used stable melanoma cell lines, parental A2058, A2058T2-1 overexpressing TIMP-2, and A2058T2R-7 underexpressing TIMP-2, to determine the TIMP-2 regulation of the NF-kappaB activity.

Results: We found that the IL-8 secretion and IL-8 mRNA expression significantly increased in the A2058T2-1 overexpressing TIMP-2. TIMP-2 overexpressed cells had the lower basal level of IkappaBalpha, the inhibitor of NF-kappaB, compared to the parental A2058 cells. The transcriptional NF-kappaB activity was increased by the TIMP-2 overexpression. In contrast, A2058T2R-7 underexpressing TIMP-2 had the similar NF-kappaB activity as that in the parental A2058 cell. The apoptotic cells induced by TNF were less in TIMP-2 over-expression cells compared to those in the parental A2058 cells. TIMP-2 over-expression was able to protect cells from apoptosis.

Conclusion: Our data demonstrate that the expression level of TIMP-2 protein can directly modulate the NF-kappaB pathway in human melanoma cells.