Mitochondrial Superoxide Dismutase Has a Protumorigenic Role in Ovarian Clear Cell Carcinoma

Abstract

Epithelial ovarian cancer (EOC) is the fourth leading cause of death due to cancer in women and comprises distinct histological 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 to 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 pro-tumorigenic and -metastatic 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. Secondly, Sod2 alters the steady-state ROS balance to drive H2O2-mediated migration. While this higher steady-state H2O2 drives pro-metastatic 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 histological EOC subtype.

Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells

“…BAR exposure increased Mitosox oxidation and depleted GSH, indicative of an oxidative stress environment. In a self-perpetuating loop, the associated increase in mitochondrial superoxide following BAR exposure may contribute to metabolic inhibition and probably impaired migration as previously described in ovarian carcinoma [20]. In combination, the loss of glycolytic capacity that was seen after BAR treatment in our study, suggests that in conditions of increased metabolic demand, such as migration, the cell is compromised.…”

“…Cell migration determines the energetic requirements of cancer cells [21] and in turn, migration is modulated by energy availability [20]. Mitochondria are important players for the maintenance of biosynthetic and energetic capacities of cells.…”

Mitochondrial ROS control of cancer

“…SOD2 contributes to the regulation of cell proliferation, transformation, migration, invasion and angiogenesis primarily through the redox-dependent modulation of the transcription factors NF-KB, HIF-1, AP-1 and p53 100,102–104 . SOD2 deficiency has been shown to have both pro- and antitumorigenic activity 102,105–107 . High SOD2 expression can inhibit cell proliferation directly 108 or sensitize cells to the cytotoxicity of the anti-cancer drugs 109 .…”

Mitochondrial determinants of cancer health disparities

“…Under high ROS conditions, however, the scavenging properties of SOD2 prevent ROS-induced apoptosis and thereby allow malignant cells to survive [151]. Likewise, in breast cancers and skin carcinomas, SOD2 is associated with a protective effect [209], but it has a pro-tumorigenic function in ovarian clear cell carcinoma [141]. …”