FIG. 6.

SOD2 and SOD3 in cell metastasis and in cell survival. (A) SOD2 promotes metastatic signaling molecule activation and inhibits apoptosis by downregulating caspase 3 and TRAIL, and by upregulating EMT mediating proteins and MMPs. (B) RTK-SRC-RAS-ERK1/2, GPCR-cAMP-PKA, and GPCR-PLC-Ca²⁺ signaling activate SOD3 production, thereby increasing cell proliferation and survival. Positive feedback signaling increases RTK phosphorylation and RAS GTP loading, thus maintaining activity of the RAS-ERK1/2 cascade. (C) RAS controls SOD3 expression through epigenetics, by p38MAPK activation, and by the PI3K-AKT-FOXO3a pathway. PI3K-AKT activation causes phosphorylation of the transcription factor, FOXO3a, resulting in its transfer from the nucleus to the cytoplasm, thereby increasing mir21 synthesis, which targets SOD3 mRNA. EMT, epithelial/mesenchymal transition; FOXO, forkhead box family; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; TRAIL, TNF-related apoptosis-inducing ligand.