Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antioxidant enzyme levels were determined in kidneys during estrogen-induced cortical renal tumorigenesis in male Syrian hamsters. The activity of these enzymes in renal tumors were compared to those in the kidney cortex of untreated male castrated hamsters of different ages and in age-matched animals treated with diethylstilbestrol (DES) for varying periods. A transient increase in kidney Mn superoxide dismutase (MnSOD) and total SOD activity was seen after 1.5 and 3.1 months of DES treatment compared to untreated controls. However, after 4.4 months of DES exposure the activities of these antioxidant enzymes fell below untreated levels. The level of MnSOD and CuZnSOD was 3- to 10-fold lower compared to castrated male renal cortical values in DES-induced primary, serially transplanted and in autonomous renal tumour variants. Catalase activity declined steadily at 1.5 to 4.4 months of DES treatment. Low levels of catalase activity were found in all tumors examined. In general, Western blot analysis of immunoreactive proteins confirmed these findings, indicating that the low enzyme activities were due to low levels of enzyme proteins. Immunohistochemistry of the earliest tumor foci exhibited negligible antioxidant enzyme activity. The levels of these antioxidant enzymes were similar in all tumors surveyed, both primary and autonomous variants and in newborn kidneys, and they were about 10-fold lower than in normal kidney cortex or isolated proximal tubules.
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PMID:Superoxide dismutase and catalase levels during estrogen-induced renal tumorigenesis, in renal tumors and their autonomous variants in the Syrian hamster. 204 4

MnSOD is an antioxidant enzyme whose decrease in activity appears involved in tumorigenesis. We had previously reported the production of a monoclonal antibody, named 35.8, against rat MnSOD. In the present paper we show that it recognizes human and mouse MnSODs, although with different detection limits. We also use the antibody for immunofluorescence studies and observed that the antibody yields a positive staining of a non-nuclear protein, in rat and human organs where high concentration of MnSOD activity have been reported, and a lack of staining in rat kidney where MnSOD activity is decreased. Two tumors, an experimental rat hepatocarcinoma and a human liver metastasis from a gastrointestinal adenocarcinoma, are found negative for immunostaining.
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PMID:Monoclonal antibody 35.8 recognizes human, mouse and rat MnSODs in western blot and immunostaining. 808 Dec

Epidemiologic studies indicate that most risk factors for breast cancer are related to reproductive and hormonal factors. For a number of years, the mechanism for estrogens in carcinogenesis was thought to be that of mitotic stimulation, with the growth promotion of ductal epithelial cells harboring precursor mutations in the breast. However, evidence is now available that estrogens may act as initiators of cellular alterations and tumorigenesis. Investigation and measurement of serum levels of estrogens in epidemiologic studies may, therefore, be misleading, because they may reflect levels quite different from those of hormone metabolites to which the target tissue is exposed. Proportions of hormone metabolites may be estimated by evaluation of associations between breast cancer risk and genetic polymorphisms in enzymes involved in hormone metabolism. A number of molecular epidemiologic studies have been conducted to evaluate associations between polymorphic genes involved in steroid hormone metabolism (i.e., CYP17, COMT, CYP1A1, CYP19, GST, and MnSOD) that may account for a proportion of enzymatic variability, and results are discussed in this review. There are strengths and limitations to such an approach, foremost of which may be the lack of insight into the extent to which individual variability in estrogen exposure may be explained by allelic variation. Variability in other endogenous and exogenous factors that impact parent hormones and their metabolites along activation and conjugation pathways may also affect associations in case-control comparisons. This and other possible reasons for inconsistencies in results of molecular epidemiologic studies are discussed. Contributions from population-based studies and those from the laboratory may together move this field ahead and more clearly elucidate the basis of hormonally related cancers, identifying etiologic factors and susceptible populations for preventive strategies.
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PMID:Molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer. 1096 24

We address the issue of the role of manganese superoxide dismutase in tumorigenesis by studying a relatively homogeneous group of tumours for the correlation between amount of this anti-oxidant enzyme and prognosis. The clinical outcome of 30 patients affected by glioblastomas whose manganese superoxide dismutase content had been established at the time of first diagnosis is compared. When the survival of patients is stratified according to manganese superoxide dismutase level in the tumour, a link of these levels and prognosis can be observed. Patients with high levels of manganese superoxide dismutase show a median survival time of 6.11 months, while patients whose tumours display a low amount of MnSOD have a median survival time of 12.17 months. To assess the upstream mechanisms that sustain the increase in manganese superoxide dismutase content in brain neuroepithelial tumours, we also studied the expression of p53 in a series of 17 astrocytomas of various grading. In all tested astrocytomas, high manganese superoxide dismutase content is associated with cytoplasmic accumulation of p53. Thus glioblastomas can be divided into two distinct groups on the basis of their content of manganese superoxide dismutase, having 'better' or 'worse' prognosis, respectively. The use of this protein as a marker may help to define therapeutic strategies in the clinical management of glioblastoma.
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PMID:The level of manganese superoxide dismutase content is an independent prognostic factor for glioblastoma. Biological mechanisms and clinical implications. 1120 49

Forkhead box transcription factor FOXO3A, an important regulator of cellular function, is thought to act as a tumor suppressor. We studied whether alterations in FOXO3A activity occur in prostate tumorigenesis. Our studies demonstrate that FOXO3A activity is negatively regulated by Akt/PKB through posttranslational modifications. In prostate cancer cells, Akt activation causes increased accumulation of FOXO3A and its binding chaperone protein 14-3-3 in the cytosol. Higher levels of FOXO3A in the cytosol correlated with phosphorylation at Ser253, which accounted for its nuclear exclusion. Dominant negative Akt approach in PC-3 cells increased FOXO3A accumulation in the nucleus, causing upregulation of the downstream target, MnSOD. Conversely, stable DU145-Akt over-expressing cells exhibited decreased FOXO3A levels in the nucleus. Similar findings were noted in prostate tumor specimens, in which marked cytoplasmic accumulation of FOXO3A and 14-3-3 in prostate tumors was observed with increasing Gleason grade, in contrast to exclusively nuclear accumulation in benign prostate cells. These findings correlate with decreased FOXO3A DNA binding activity along with down-modulation of FOXO3A transcriptional activity with increasing tumor grade. Our findings demonstrate that tumor associated alterations and redistribution of FOXO3A are frequent events in the etiology of prostate cancer.
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PMID:Deregulation of FOXO3A during prostate cancer progression. 1942 79

Despite improvements in diagnosis of advanced prostate cancer (PCa), treatment is not efficient and 5-year survival is still low. Initially, the less abundant of cell types, neuroendocrine cells (NE), are involved in regulatory process but their physiological role is not fully understood. Among others, an increase in NE cells along with tumor progression has been commonly reported but their role in tumorigenesis or the molecular mechanisms of transdifferentiation is still a matter of debate. We have used human PCa cells (LNCaP) induced to differentiate to NE cells with several stimuli: androgen withdrawal, cyclic AMP or treatment with the antioxidant pineal hormone melatonin. PCa patients' specimens were also analyzed by western blotting and by immunocytochemistry. NE-like LNCaP cells express high levels of mitochondrial superoxide dismutase (MnSOD/SOD2) in addition to NE markers. MnSOD upregulation is mediated by NFkappaB transcription factor, mainly through p65 translocation into the nuclei. More importantly, overexpression of MnSOD induces the rise of NE-markers in LNCaP cells, showing that MnSOD upregulation might be instrumental for NE differentiation in PCa cells. Furthermore, MnSOD is highly expressed in advanced tumors of patients' when compared with control, nonpathological samples or with low-grade tumors, along with the presence of synaptophysin, a common NE marker. Also, fluorescence immunohistochemical analysis revealed that MnSOD colocalizes with NE markers in most of NE cells observed in PCa specimens. The present findings indicate that MnSOD is essential for NE transdifferentiation and mediates in part the differentiation process, which appears also to be critical in vivo.
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PMID:Upregulation of manganese superoxide dismutase (SOD2) is a common pathway for neuroendocrine differentiation in prostate cancer cells. 1950 53

To test the impact of increased mitochondrial oxidative stress as a mechanism underlying aging and age-related pathologies, we generated mice with a combined deficiency in two mitochondrial-localized antioxidant enzymes, Mn superoxide dismutase (MnSOD) and glutathione peroxidase-1 (Gpx-1). We compared life span, pathology, and oxidative damage in Gpx1(-/-), Sod2(+/-)Gpx1(+/-), Sod2(+/-)Gpx1(-/-), and wild-type control mice. Oxidative damage was elevated in Sod2(+/-)Gpx1(-/-) mice, as shown by increased DNA oxidation in liver and skeletal muscle and increased protein oxidation in brain. Surprisingly, Sod2(+/-)Gpx1(-/-) mice showed no reduction in life span, despite increased levels of oxidative damage. Consistent with the important role for oxidative stress in tumorigenesis during aging, the incidence of neoplasms was significantly increased in the older Sod2(+/-)Gpx1(-/-) mice (28-30 months). Thus, these data do not support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice and do not support the oxidative stress theory of aging.
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PMID:Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. 1977 19

Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression. Reactive oxygen species (ROS) have been implicated in the induction of premature senescence response. Several pathological disorders such as cancer, aging and age related neurological abnormalities have been linked to ROS deregulation. Here, we discuss how Damaged DNA binding Protein-2 (DDB2), a nucleotide excision repair protein, plays an important role in ROS regulation by epigenetically repressing the antioxidant genes MnSOD and Catalase. We further revisit a model in which DDB2 plays an instrumental role in DNA damage induced ROS accumulation, ROS induced premature senescence and inhibition of skin tumorigenesis.
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PMID:Damaged DNA binding protein 2 in reactive oxygen species (ROS) regulation and premature senescence. 2310 35

Colorectal cancer (CRC) is a common malignancy. Many reports have implicated aberrant mitochondrial activity in the progression of CRC, with particular emphasis on the dysregulation of redox signaling and oxidative stress. In this study, we focused on manganese superoxide dismutase (MnSOD/SOD2), a key antioxidant enzyme, which maintains intracellular redox homeostasis. Current literature presents conflicting mechanisms for how SOD2 influences tumorigenesis and tumor progression. Here, we explored the role of SOD2 in CRC specifically. We found high levels of SOD2 expression in CRC tissues. We carried out a series of experiments to determine whether knockdown of SOD2 expression in CRC cell lines would reverse features of tumorigenesis. We found that reduced SOD2 expression decreased cell proliferation, migration, and invasion activity in CRC cells. Results from an additional series of experiments on mitochondrial function implicated a dual role for SOD2 in promoting CRC progression. First, proper level of SOD2 helped CRC cells maintain mitochondrial function by disposal of superoxide (O2 .- ). Second, over-expression of SOD2 induced H2 O2 -mediated tumorigenesis by upregulating AMPK and glycolysis. Our results indicate that SOD2 may promote the occurrence and development of CRC by regulating the energy metabolism mediated by AMPK signaling pathways.
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PMID:Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK-mediated energy metabolism. 3214 14