SOD2 to SOD1 switch in breast cancer [Molecular Bases of Disease]

January 21st, 2014 by Papa, L., Hahn, M., Marsh, E. L., Evans, B. S., Germain, D.

Cancer cells are characterized by elevated levels of reactive oxygen species (ROS), which are produced mainly by the mitochondria. The dismutase SOD2 localizes in the matrix and is a major anti-oxidant. The activity of SOD2 is regulated by the deacetylase SIRT3. Recent reports indicated that SIRT3 is decreased in 87% of breast cancers implying that the activity of SOD2 is compromised. The resulting elevation in ROS was shown to be essential for the metabolic reprograming toward glycolysis. Here, we show that SOD2 itself is down-regulated in breast cancer cell lines. Further, activation of oncogenes, such as Ras, promotes the rapid down-regulation of SOD2. Since in absence of SOD2, superoxide levels are elevated in the matrix, we reasoned that mechanisms must exist to retain superoxide low in other cellular compartments especially in the inter-membrane space of the mitochondrial to avoid irreversible damage. The dismutase SOD1 also acts as an anti-oxidant but it localizes to the cytoplasm and the inter-membrane space of the mitochondria. We report here that loss of SOD2 correlates with the overexpression of SOD1. Further, we show that mitochondrial SOD1 is the main dismutase activity in breast cancer cells but not in non-transformed cells. In addition, we show that the SOD1 inhibitor LCS-1 leads to a drastic fragmentation and swelling of the matrix suggesting that in absence of SOD2, SOD1 is required to maintain the integrity of the organelle. We propose that by analogy to the cadherin-switch during epithelial-mesenchymal transition, that cancer cells also undergo a SOD-switch during transformation.