Modulation of MnSOD in Cancer:Epidemiological and Experimental Evidence

Abstract

Since it was first observed in late 1970s that human cancers often had decreased manganese superoxide dismutase (MnSOD) protein expression and activity, extensive studies have been conducted to verify the association between MnSOD and cancer. Significance of MnSOD as a primary mitochondrial antioxidant enzyme is unquestionable; results from in vitro, in vivo and epidemiological studies are in harmony. On the contrary, studies regarding roles of MnSOD in cancer often report conflicting results. Although putative mechanisms have been proposed to explain how MnSOD regulates cellular proliferation, these mechanisms are not capitulated in epidemiological studies. This review discusses most recent epidemiological and experimental studies that examined the association between MnSOD and cancer, and describes emerging hypotheses of MnSOD as a mitochondrial redox regulatory enzyme and of how altered mitochondrial redox may affect physiology of normal as well as cancer cells.

Keywords: Cancer; Carcinogenesis; Epidemiology; Hydrogen peroxide; Mitochondria; MnSOD; Oxidative stress; Redox; Superoxide anion.

Fig. 1.. Mitochondrial antioxidant enzymes involved in the removal of superoxide anion. Mitochondrial superoxide anion (O₂˙^-) is generated as a byproduct of oxidative phosphorylation. Enzymatic conversion of O₂˙^- to H₂O₂ is catalyzed by MnSOD. H₂O₂ is further reduced to H₂O via GSH system (GPX/GR/GSH) or TXN system (PRDX3/TXNRD2/TXN2) . NADPH, the reducing equivalent for these systems is regenerated by NNT at the expense of intermembrane proton gradient and NADH. Abbreviations: MnSOD, manganese superoxide dismutase; GPX, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione; PRDX3, peroxiredoxin 3, TXNRD2, thioredoxin reductase 2; TXN2, thioredoxin 2; NNT, nicotinamide nucleotide transhydrogenase.

Fig. 2.. Regulation of MnSOD expression at gene, RNA and protein levels. Expression and activity of MnSOD can be modulated at various levels. Detailed mechanisms are described in the text. The drawing is not to the scale.

Fig. 3.. Possible cellular alterations via transiently increased MnSOD activity. Putative pathways are shown in closed lines. Down-stream events shown in dashed lines may not be required for the manifestation of physiological consequences of MnSOD overexpression. See the text for detailed information.