Deleterious MnSOD signals lead to abnormal breast cell proliferation by radiation and estrogen exposure (original) (raw)
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Two polymorphic variants of manganese superoxide dismutase (MnSOD), with either Ile or Thr at amino acid 58, (Ile 58 MnSOD or Thr 58 MnSOD), have been found in the human population. The MnSOD activity of these two variants and their effects on the malignant phenotype of human breast cancer MCF-7 cells were compared. It was demonstrated that MnSOD-overexpressing clones obtained from transfection of the two MnSOD cDNAs into MCF-7 cells had increased MnSOD immunoreactive protein and increased MnSOD activity. Cells overexpressing Ile 58 MnSOD had 3-fold higher MnSOD activity than cells overexpressing Thr 58 MnSOD in vivo at an equal MnSOD protein level. Tumor-suppressive effects of MnSOD-overexpressing cells were indicated by: (a) decreased plating efficiency; (b) elongated cell population doubling time; (c) lower clonogenic fraction in soft agar; and (d) complete inhibition or delayed onset of tumor formation in nude mice.
Radiation Research, 2011
Manganese superoxide dismutase (MnSOD) is a nuclear encoded primary antioxidant enzyme localized in mitochondria. Because expression of MnSOD plays a major role in maintaining cellular redox status and reactive oxygen species are known to play a role in signal transduction and carcinogenesis, we investigated the role of MnSOD in the development of cancer using a two-stage [7,12-dimethylbenz(a)-anthracene plus 12-Otetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis model. Female transgenic mice expressing the human MnSOD gene in the skin and their nontransgenic counterparts were used in this study. Pathological examination demonstrated significant reduction of papilloma formation in transgenic mice. Quantitative analysis of 4-hydroxy-2-nonenal-modified proteins showed greater accumulation of oxidative damage products in nontransgenic compared with transgenic mice, and this oxidative damage was demonstrated to be present in both mitochondria and nucleus. TPA increased activator protein-1 (AP-1) binding activity within6hi nnontransgenic mice, but increased AP-1 binding activity was delayed in the transgenic mice. Electrophoretic mobility shift assay, transcription of the target genes, and Western analysis studies indicated that the increased AP-1 binding activity was attributable to induction of the Jun but not the Fos protein families. Overexpression of MnSOD selectively inhibited the TPA-induced activation of protein kinase C⑀ and prevented subsequent activation of c-Jun NH 2 -terminal kinase in response to TPA. Overall, these results indicate that MnSOD regulates both cellular redox status and selectively modulates PKC⑀ signaling, thereby delaying AP-1 activation and inhibiting tumor promotion, resulting in reduction of tumors in MnSOD transgenic mice.
Journal of Biomedicine and Biotechnology, 2004
Manganese superoxide dismutase (Mn-SOD), localized at the mitochondrial matrix, has the ability to protect cells against oxidative damage. It has been reported that low levels of Mn-SOD gene expression cause the development of certain kind of tumors. On the other hand, overexpression of Mn-SOD gene may play an important role in the development of cancer. In our study, we find that Mn-SOD activity was higher in nonaggressive (MCF-7) and aggressive (BT-549 and 11-9-14) breast cancer cell lines compared to that of nontumorigenic (MCF-12A and MCF-12F) mammary epithelial cell lines. We also observed an increased expression of Mn-SOD gene in cancerous cell lines. The elevated level of SOD activity in nonaggressive and aggressive breast epithelial cell lines was associated with some changes in nucleotide sequence.
Breast cancer is one of the most common malignancies of all cancers in women worldwide. Many difficulties reside in the prediction of tumor metastatic progression because of the lack of sufficiently reliable predictive biological markers, and this is a permanent preoccupation for clinicians. Manganese superoxide dismutase (MnSOD) may represent a rational candidate as a predictive biomarker of breast tumor metastatic progression, because its gene expression is profoundly altered between early and advanced breast cancer, in contrast to expression in the normal mammary gland. In this review, we report the characterization of some gene polymorphisms and molecular mechanisms of SOD2 gene regulation, which allows a better understanding of how MnSOD is decreased in early breast cancer and increased in advanced breast cancer. Several studies display the biological significance of MnSOD level in proliferation as well as in invasive and angiogenic abilities of breast tumor cells by controlling superoxide anion radical (O 2
2004
The most important cellular protective mechanisms against oxidative stress are antioxidant enzymes. Their action is based on decomposal of reactive oxygen species (ROS) and their transformation to H 2 O 2. Within the mitochondria manganese superoxide dismutase (MnSOD) affords the major defense against ROS. In this study we investigated tissue sections from 101 breast carcinomas for the immunohistochemical expression of MnSOD protein and these results were assessed in relation to various clinicopathological parameters, in order to clarify the prognostic value of this enzyme. The possible relationship to hormone receptor content, anti-apoptotic protein bcl-2, p53 and cell proliferation was also estimated. High expression levels were observed, as 79/101 (78,2%) cases expressed strong immunoreactivity. In this study MnSOD increased in a direct relationship with tumor grade and is therefore inversely correlated with differentiation (p=0.0004). Furthermore, there was a strong positive correlation between MnSOD expression and p53 protein immunoreactivity (p=0.0029). The prognostic impact of MnSOD expression in determining the risk of recurrence and overall survival with both univariate (long-rang test) and multivariate (Cox regression) methods of analysis was statistically not significant. These results indicate that neoplastic cells in breast carcinomas retain their capability to produce MnSOD and thus protected from the possible cellular damage provoked by reactive oxygen species. In addition, MnSOD content varies according to the degree of differentiation of breast carcinoma.
2001
Manganese superoxide dismutase (MnSOD) is a nuclear encoded primary antioxidant enzyme localized in mitochondria. Because expression of MnSOD plays a major role in maintaining cellular redox status and reactive oxygen species are known to play a role in signal transduction and carcinogenesis, we investigated the role of MnSOD in the development of cancer using a two-stage [7,12-dimethylbenz(a)-anthracene plus 12-Otetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis model. Female transgenic mice expressing the human MnSOD gene in the skin and their nontransgenic counterparts were used in this study. Pathological examination demonstrated significant reduction of papilloma formation in transgenic mice. Quantitative analysis of 4-hydroxy-2-nonenal-modified proteins showed greater accumulation of oxidative damage products in nontransgenic compared with transgenic mice, and this oxidative damage was demonstrated to be present in both mitochondria and nucleus. TPA increased activator protein-1 (AP-1) binding activity within 6 h in nontransgenic mice, but increased AP-1 binding activity was delayed in the transgenic mice. Electrophoretic mobility shift assay, transcription of the target genes, and Western analysis studies indicated that the increased AP-1 binding activity was attributable to induction of the Jun but not the Fos protein families. Overexpression of MnSOD selectively inhibited the TPA-induced activation of protein kinase C⑀ and prevented subsequent activation of c-Jun NH 2 -terminal kinase in response to TPA. Overall, these results indicate that MnSOD regulates both cellular redox status and selectively modulates PKC⑀ signaling, thereby delaying AP-1 activation and inhibiting tumor promotion, resulting in reduction of tumors in MnSOD transgenic mice.
Overexpression of manganese or copper–zinc superoxide dismutase inhibits breast cancer growth
Free Radical Biology and Medicine, 2006
We have studied the effects of overexpression of superoxide dismutase (SOD), a tumor suppressor protein that dismutes superoxide radical to H 2 O 2 , on breast cancer cell growth in vitro and xenograft growth in vivo. No previous work has directly compared the growth-suppressive effects of manganese SOD (MnSOD) and copper-zinc SOD (CuZnSOD). We hypothesized that either adenoviral MnSOD (AdMnSOD) or adenoviral CuZnSOD (AdCuZnSOD) gene therapy would suppress the growth of human breast cancer cells. After determining the antioxidant profiles of three human breast cell lines, MCF 10A, MDA-MB231, and MCF-7, we measured the effects of MnSOD or CuZnSOD overexpression on cell growth and survival in vitro and in vivo. Results demonstrated that infection with AdMnSOD or AdCuZnSOD increased the activity of the respective enzyme in all three cell lines. In vitro, overexpression of MnSOD or CuZnSOD decreased not only cell growth but also clonogenic survival in a dose-and transgene-dependent manner. In vivo, treatment of tumors with AdMnSOD or AdCuZnSOD decreased xenograft growth compared to controls. The first direct comparison of MnSOD to CuZnSOD overexpression indicated that CuZnSOD and MnSOD were similarly effective at suppressing cancer cell growth.
Advances in Animal and Veterinary Sciences, 2016
C anine mammary cancer is an important neoplastic condition of female dogs (Davidson, 2003; Murphy, 2008; Salas et al., 2015) accounting for more than 40% of all tumours diagnosed (Sleeckx et al., 2011; Beck et al., 2013). The mortality rates in dogs suffering with canine mammary cancer are atleast three times higher than human breast cancer (Egenvall et al., 2005; Shafiee et al., 2013). In recent years there has been alarming increase in incidence of canine mammary tumor cases due to interaction between genetic and environmental factors (Pharoah et al., 2004; Wang et al., 2012). Cancer onset typically encompasses alterations in the cellular growth and proliferation, production of reactive oxygen species (ROS), and DNA damage. Reactive oxygen species (ROS) produced endogenously play important role in development of cancers by inducing DNA damage and stimulating cell proliferation which leads to tumour promotion (Clair et al., 1996). Higher levels of ROS contribute to genetic instability, which ultimately results in the stepwise process of carcinogenesis. Further ROS also activate various cancer signalling pathways and transcription factors in tumour cells regulating proliferation, me-Short Communication Abstract | Cancer onset typically encompasses alterations in cellular proliferation, production of reactive oxygen species (ROS), and DNA damage. Manganese superoxide dismutase (MnSOD) is one of the key enzymes for controlling oxidative stress. The role of MnSOD in cancer development is complex. Although initially considered as a tumour suppressor protein, recently it has been looked upon as a potential marker for cancer metastasis. Though MnSOD has been studied extensively in human cancers, not much work has been done for elucidating its role in dog cancers. Further dog MnSOD gene has not been sequenced so far, although dog MnSOD gene sequence predicted using computational biology approaches is present in the GenBank database. Therefore in this study, full-length ORF of sod2 gene, a gene encoding MnSOD enzyme, from a case of canine mixed mammary capillary cystic adenocarcinoma was cloned and sequenced. The sequence showed 100% similarity with the predicted dog MnSOD sequence present in GenBank database based on computational algorithms. Comparison of deduced amino acid sequence from Canis lupus familiaris and Homo sapiens revealed 92% similarity, confirming the conserved nature of the protein. Further the full-length MnSOD was expressed in E.coli and purified protein was isolated successfully. The recombinant MnSOD from dog offers a new tool for studying effect of the anti-oxidant enzyme on dog cancer cells, wound healing and other disorders.