Superoxide dismutase (SOD) catalyses the dismutation of superoxide radical to hydrogen peroxide and oxygen. Three isoforms exist in human cells. Which metalloenzyme is the mitochondrial isoform (MnSOD/SOD2), and why is its upregulation important in cancer biology?

• A SOD2 uses manganese as its metal centre; in some cancers it is downregulated (promoting ROS-driven mutagenesis) while in therapy-resistant cancers it is upregulated to detoxify treatment-induced ROS and promote survival ✓
• B SOD2 uses copper/zinc and is uniformly overexpressed in all cancers to neutralise chemotherapy
• C SOD2 uses iron as its metal centre and is silenced by hypoxia-inducible factor 1-alpha in all tumour types
• D SOD2 is the extracellular isoform secreted by hepatocytes that primarily scavenges vascular superoxide

Explanation

MnSOD (SOD2) is the mitochondrial matrix isoform, using Mn3+/Mn2+ redox cycling to convert O2•− to H2O2 and O2. In cancer biology, SOD2 has a paradoxical dual role: early carcinogenesis is favoured by low SOD2 expression (allowing ROS-driven oxidative DNA damage and mutation). However, in advanced/therapy-resistant cancers, SOD2 is often upregulated, detoxifying mitochondrial ROS generated by radiation or cytotoxic drugs and thereby promoting tumour cell survival. This is why SOD2 expression level correlates with prognosis in a cancer-type-dependent manner. CuZnSOD (SOD1) is cytoplasmic; extracellular SOD (SOD3) is secreted and uses CuZn.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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