# Vitamin D Regulation of a SOD1-to-SOD2 Antioxidative Switch to Prevent Bone Cancer
## 3 Discussion  
It has long been recognized that vitamin D has non-calcemic functions in controlling the cell cycle, differentiation and apoptosis, and its analogues are used in cancer treatment [17; 51; 52]. The anti-neoplastic mechanisms of vitamin D at the cellular and molecular levels are becoming clearer, yet not fully understood. For example, the tumor suppressor protein p53 upregulates the VDR in certain cancer types to inhibit cancer progression [53]. In contrast, many cancers harbor mutated p53 proteins  
Figure 4: Schema representing the SOD1-to-SOD2 switch in MG-63 osteosarcoma cells after vitamin D treatment. Cancer cells generally express elevated levels of SOD1 (superoxide dismutase 1) compared to SOD2 (superoxide dismutase 2) with respect to non-tumorigenic cells. This indicates a higher reactive oxygen species (ROS) burden in the cancer cells. Vitamin D treatment in a dose- and time-dependent manner promotes an increase in SOD2 levels, with concomitant decreases in antioxidant CAT (catalase) and SOD1 levels, indicative of mitochondrial stress relief via enhanced SOD2 activity. that can physically interact with the VDR and convert it into an anti-apoptotic agent [54]. Although p53 is a major regulator of cancer transformation, it appears to not be a factor in terms of how vitamin D regulates MG-63 osteosarcoma progression since these cells lack p53 [55]. Understanding how vitamin D can regulate dynamic cancer-related processes is central to applications toward specialized cancer treatment [51]. The major finding of this paper is that MG-63 osteosarcoma cells can respond to adaptive signals such as vitamin D to suppress the transformation process by upregulation of SOD2. The degree to which the vitamin D-SOD network offers specific cytoprotective and antioxidative effects is unclear and should be the focus of future studies. Importantly, this form of regulation is tightly controlled in a 1,25D\({}_{3}\) concentration and time dependent manner which argues for maintenance of proper vitamin D levels in the body. The importance of SODs are reflected in mice either lacking mitochondrial or cytosolic SODs that die around 21 days after birth or exhibit milder phenotypes, respectively, such as the development of cancer in time [56]. It appears if SOD levels and distributions are unchecked, this can contribute to mitochondrial damage and eventual cancer transformation [30]. Recent studies using both human and murine cancer models indicate that the expression of SOD2 is rapidly reduced upon activation of various oncogenes [43], thus compromising it's cytoprotective and antioxidative roles, presumably within the mitochondria. Thus, strategies to induce SOD2 may be an effective way to limit cancer transformation. On the other hand, SOD1 is overexpressed in a majority of mammary tumor models driven by various oncogenes [43]. It is possible that mitochondrial SOD1 may be necessary to maintain the integrity of the organelle when the levels of SOD2 are compromised during transformation. Indeed, after 10 nM 1,25D\({}_{3}\) treatment for 48 h there was a cumulative increase in the combined SOD1 and SOD2 transcript amounts compared to untreated MG-63 cells (Figure 3F). Nevertheless, the consensus is that, in non-tumorigenic cells, SOD2 levels are elevated while SOD1 levels are kept low [43], suggesting that mitochondrial protection from ROS is critical in the natural high respiratory state. It was recently shown that pharmacological inhibition of SOD1 results in fragmented and dilated cristae of mitochondria in a breast cancer cell line (MDA-MB-231) [43], suggesting the critical role of SOD1 protection from mitochondrial ROS toxic effects during transformation. However, SOD1 inhibition within non-tumorigenic cells did not alter morphological features of the mitochondria [43], presumably due to protection from the known increased endogenous levels of SOD2. These findings correlate with the long recognized understanding that cancer cells are characterized by elevated levels of ROS [57].