These studies will evaluate the role of the mitochondrial manganese superoxide dismutase (Sod2) in the regulation of matrix metalloproteinase (MMP) expression and metastatic invasion. We have established that the Sod2-dependent H202 production is sufficient and required for MMP-1 expression. The ability of Sod2 overexpression to modulate MMP expression appears to be dependent on signaling through Ras and the ERK1/2 cascade. This signaling cascade may be utilized under a variety of conditions where Sod2 levels are elevated. We have also established that invasion, metastasis and MMP expression are enhanced in an H202-dependent fashion when Sod2 is overexpressed. These observations may explain a number of reports suggesting that Sod2 overexpression is linked to an increase in metastatic cancers. More importantly we have shown that Sod2 and MMP-1 functionally interact. This latter observation is quite provocative, as SNPs in either of these proteins have independently been linked to increased incidence of various forms of cancer. It has been proposed that the Sod2 polymorphism increases its activity. Our findings indicate that increases in Sod2 activity can increase the transcriptional activity of both the native and polymorphic MMP-1 promoter. Furthermore, only subtle changes in Sod2 levels are required to modulate MMP-1 expression. The proposed studies will: (1) establish the link between Sod2, MMPs and metastasis, (2) define the molecular mechanisms that modulate MMP expression in response to Sod2-dependent production of H2O2, (3) determine if a synergy between the Sod2 and MMP-1 levels or polymorphisms exist, and (4) develop redox-based adenoviral vectors that target metastatic tumor cells for destruction.
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