Mitochondrial superoxide dismutase has a protumorigenic role in ovarian clear cell carcinoma

Epithelial ovarian cancer (EOC) is the fourth leading cause of death due to cancer in women and comprises distinct histologic subtypes, which vary widely in their genetic profiles and tissues of origin. It is therefore imperative to understand the etiology of these distinct diseases. Ovarian clear cell carcinoma (OCCC), a very aggressive subtype, comprises >10% of EOCs. In the present study, we show that mitochondrial superoxide dismutase (Sod2) is highly expressed in OCCC compared with other EOC subtypes. Sod2 is an antioxidant enzyme that converts highly reactive superoxide (O₂^•-) to hydrogen peroxide (H₂O₂) and oxygen (O₂), and our data demonstrate that Sod2 is protumorigenic and prometastatic in OCCC. Inhibiting Sod2 expression reduces OCCC ES-2 cell tumor growth and metastasis in a chorioallantoic membrane (CAM) model. Similarly, cell proliferation, migration, spheroid attachment and outgrowth on collagen, and Akt phosphorylation are significantly decreased with reduced expression of Sod2. Mechanistically, we show that Sod2 has a dual function in supporting OCCC tumorigenicity and metastatic spread. First, Sod2 maintains highly functional mitochondria, by scavenging O₂^•-, to support the high metabolic activity of OCCC. Second, Sod2 alters the steady-state ROS balance to drive H₂O₂-mediated migration. While this higher steady-state H₂O₂ drives prometastatic behavior, it also presents a doubled-edged sword for OCCC, as it pushed the intracellular H₂O₂ threshold to enable more rapid killing by exogenous sources of H₂O₂. Understanding the complex interaction of antioxidants and ROS may provide novel therapeutic strategies to pursue for the treatment of this histologic EOC subtype.