A NOVEL PRO-OXIDANT ROLE OF GELSOLIN IN CANCER CELL INVASION

Abstract

Although gelsolin is often implicated in cancer cell invasion, the mechanisms remain poorly understood. We have identified a new role of gelsolin in creating a pro-oxidant milieu thereby enhancing cancer cell invasion. Increased gelsolin expression in HCT116 results in heightened ROS levels, particularly the superoxides (O2-) as well as increased invasion; whereas silencing of gelsolin reduces O2- levels and invasion. Inhbition of O2- produciton using diphenyleneiodonium significanlty attenuates invasion in gelsolin-overexpresing HCT116 cells. Consistently, the invasive capacities of gelsolin-deficient cells were rescued by increasing the O2- levels in these cells. Furthermore we show that gelsolin overexpression suppresses the activity of the antioxidant Cu/Zn SOD, possibly by binding to it. The impairment of Cu/Zn SOD activity provides a mechanistic explanation for the elevated amount of intracellular O2- in gelsolin-overexpressing cells. Therefore, our findings demonstrate a new insight into the role of gelsolin in cancer cell invasion through upregulation of O2- levels.