Investigating the role of cofilin oxidation in cancer cell migration and invasion

Cancer cell invasion and metastasis is one of the hallmarks of cancer and is frequently the fatal stage in disease progression. One of the key cellular processes underlying invasion and metastasis is cell migration, which is highly dependent on dynamic changes in the actin cytoskeleton. Reactive oxygen species (ROS) are frequently found at elevated levels in cancer and promote disease progression particularly by increasing invasion and metastasis. Although it is known that ROS, specifically H2O2, mediate their downstream effects through the oxidation of proteins on key cysteine residues, very little is known about the direct protein targets of ROS and how the resulting protein oxidation might contribute to cell migration, invasion and metastasis. I have demonstrated that the ROS, H2O2, is produced at increased levels in migrating cells, predominantly at the tips of cell protrusions. Furthermore, I established that protein oxidation is increased in migrating cells and identified the actin binding protein cofilin as one of these oxidised proteins. I have also provided evidence that, when oxidised, cofilin forms oligomers and has a reduced ability to decrease F-actin levels in vitro, which was dependent on cysteine residues 139 and 147. Moreover, I have shown that the oxidation of these cysteine residues is important for directional cell migration and adhesion. Taken together my results provide a direct link between the increased production of ROS at the leading edge of migrating cells and dynamic changes in the actin cytoskeleton that take place in this region to enable cell migration. As the invasion and metastasis of cancer is largely dependent on cell migration, these findings could potentially lead to the development of new ways to target this stage in disease progression