The SNPs superoxide dismutase 2 (SOD2) rs4880 (P=0.005) and interleukin-13 (IL13) rs1800925 (P=0.0008) were significantly associated with tumor response to chemoradiation.
The SOD2rs4880 CT + CC genotypes were significantly associated with a high level of lymph node metastasis (P = .023), whereas the GSTP1 rs1695 GA + GG genotypes were significantly associated with larger tumor size (>5 cm long; P = .048).
Superoxide dismutase-2 (SOD2), which encodes the antioxidant enzyme manganese superoxide dismutase (MnSOD), is a putative tumor suppressor gene whose loss of expression is associated with the malignant phenotype.
Manganese superoxide dismutase (SOD2) catalyzes the dismutation of superoxide radicals, a major type of ROS, into hydrogen peroxide. p53 is a tumor suppressor gene, and X-ray cross-complementing group 1 (XRCC1) is involved in the base-excision repair of ROS-induced DNA damage.
Complete sequencing of the two Mn-SOD expression forms unambiguously characterizes this enzyme from a tumor cell line providing evidence that can be used for generation of antibodies and allowing conformational studies.
Superoxide dismutase 2 (SOD2) was found to exert tumour suppressive effect in basic research, but increased SOD2 protein level was associated with higher aggressiveness of human astrocytomas.
Male and female mice receiving 1.0 Gy TBI showed radiation-induced life shortening after 120 days that was decreased by MnSOD-PL administration and that was not associated with an increase in rate of tumor-associated death.
Transfection of SOD-2 in M12 cells markedly decreased tumor growth, apoptosis, G1 delay in the cell cycle, and expression of senescence associated beta-galactosidase.
These results suggest that levels of MnSOD are highly regulated within C8161 melanoma cells and that SOD2 does not suppress tumor formation nor metastatic potential in all human melanomas.
Only the tumor cells died following treatment with rMnSOD-Lp-CC; molecular analysis revealed that its addition generated an increasing expression of Erk-2 and Bax products, which could be inhibited only by a selective MAP/ERK kinase inhibitor (PD98059), revealing that rMnSOD-Lp-CC has an apoptotic function, exactly as occurs when using the cisplatin alone.
Moreover, future work examining the spatio-temporal nature of SOD2 regulation in the context of changing tumor microenvironments is necessary to allows us to better design oxidant- or antioxidant-based therapeutic strategies that target the adaptable antioxidant repertoire of tumor cells.
These results suggest that CuZnSOD and MnSOD may suppress tumour growth through inhibiting metabolic stress-induced necrosis and HMGB1 release via inhibiting metabolic stress-induced mitochondrial ROS production.
In order to understand the molecular mechanism of this anti-tumor effect, we asked whether tumor suppressor gene(s), especially the ones inhibiting tumor invasion and motility, are involved in MnSOD-induced tumor suppression.
This review presents recent evidence and emerging questions regarding the p53-MnSOD-p66shc connection, and discusses how dissection of a circuitry comprising a tumor suppressor, an antioxidant, and a molecule regulating cell survival and mammalian lifespan can provide a framework to address important aspects related to the intricate connection between metabolism, aging, and cancer.
These results allow us to reconstruct the sequence of events leading to the decrease of SOD2, a possible tumor-suppressor gene, during the process of SV40-transformation of human fibroblasts.