Inhibition of Cell Growth by Overexpression of Manganese Superoxide Dismutase (MnSOD) in Human Pancreatic Carcinoma

Ough, Matthew; Lewis, Anne Marie; Zhang, Yuping; Hinkhouse, Marilyn M.; Ritchie, Justine M.; Oberley, Larry W.; Cullen, Joseph J.

doi:10.1080/10715760400017376

Cited by 71 publications

(58 citation statements)

References 17 publications

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“…While the magnitude and persistence of the effect were similar for both HMEC and SA-NH cells (see Fig. 2, Table 2), the inherent endogenous SOD2 activity measured was greater in non-malignant HMEC, 0.048 ± 0.02 U/10 6 cells, than in mouse tumor SA-NH cells, 0.013 ± 0.002 U/10 6 cells, consistent with reports that cancer cells compared to normal cells are generally low in the enzymatic activities of both SOD1 and SOD2 (30,32,33). SA-NH cells also appeared to require a relatively greater elevation in SOD2 activity than did HMEC to achieve comparable levels of increased radiation protection (see Fig.…”

Section: Discussionsupporting

confidence: 76%

Maintenance of Manganese Superoxide Dismutase (SOD2)-Mediated Delayed Radioprotection Induced by Repeated Administration of the Free Thiol Form of Amifostine

Murley¹,

Nantajit

Baker³

et al. 2008

Radiation Research

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Thiol-containing drugs such as WR1065, the free thiol form of amifostine, have been shown to induce a delayed radioprotective effect in both malignant and non-malignant cells. In mammalian cells exposed to a dose as low as 40 μM WR1065, the redox-sensitive nuclear transcription factor κB (NFκB) is activated, leading to an elevation in the expression of the antioxidant gene manganese superoxide dismutase (SOD2) and a concomitant increase in active SOD2 enzyme levels that peaks 24 to 32 h later. Exposure of cells to ionizing radiation during the period of elevated SOD2 enzymatic activity results in an enhanced radiation resistance. This is seen as an increase in surviving fraction as determined by standard colony formation assays. To determine whether this delayed radioprotection can be maintained over a prolonged period in cells of either malignant or nonmalignant origin, both human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were grown to confluence and exposed to 40 μM WR1065 using three administration protocols: (1) daily drug exposure for 10 days followed each day by irradiation with 2 Gy; (2) drug exposure once every 48 h followed by irradiation with 2 Gy 48 h later for 14 days; and (3) drug exposure every 72 h followed by irradiation with 2 Gy 72 h later for 12 days. As a function of each experimental condition, cell numbers and associated SOD2 enzymatic activities were measured at the time of each irradiation. None of the treatment conditions were toxic to either HMEC or SA-NH cells. SOD2 activity was elevated 5.3-and 1.8-fold over background on average for HMEC exposed to 40 μM WR1065 every 24 or 48 h, respectively. Likewise, SOD2 activity was elevated in SA-NH mouse sarcoma cells 7.8-and 4.9-fold after daily exposure to WR1065 or exposure to WR1065 once every 48 h, respectively. Both HMEC and SA-NH cells exhibited enhanced radiation resistance that correlated with the increase in SOD2 activity. The average respective increases in cell survival were 1.33 ± 0.01 (SEM), 1.23 ± 0.01 and 1.04 ± 0.01 for HMEC exposed to WR1065 every 24, 48 and 72 h, respectively, and 1.27 ± 0.01, 1.18 ± 0.02 and 1.02 ± 0.02 for SA-NH cells exposed to WR1065 every 24, 48 and 72 h, respectively. Both the elevation in WR1065-induced SOD2 enzymatic activity and the corresponding increase in radiation resistance were completely inhibited in HMEC and SA-NH cells transfected with human or mouse SOD2 siRNA oligomers and irradiated 24 h later. These data demonstrate that a delayed radioprotective effect can be induced and maintained over a prolonged period in both non-malignant and malignant cells exposed to thiol-containing drugs such as WR1065. For non-malignant cells this represents a novel paradigm for radiation protection. The ability of WR1065 to induce a persistent elevated radiation resistance in malignant cells, however,

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Section: Discussionsupporting

confidence: 76%

Maintenance of Manganese Superoxide Dismutase (SOD2)-Mediated Delayed Radioprotection Induced by Repeated Administration of the Free Thiol Form of Amifostine

Murley¹,

Nantajit

Baker³

et al. 2008

Radiation Research

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“…Additionally, polymorphisms in this gene have been associated with cancer (60). Some evidence from in vitro studies suggests that superoxide dismutase 2 may act as a tumor suppression gene (61)(62)(63)(64)(65), with increased expression of superoxide dismutase 2 having been shown to suppress the cancer phenotype in a large number of mammalian tumor cells, including human melanoma cells (61,62). We observed down-regulated expression of superoxide dismutase 2 in individuals with skin lesions, which may indicate an increased vulnerability to reactive oxygen species generated by arsenic in individuals with manifest arsenic toxicity.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiles in Peripheral Lymphocytes by Arsenic Exposure and Skin Lesion Status in a Bangladeshi Population

Argos¹,

Kibriya²,

Parvez

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Millions of individuals worldwide are chronically exposed to arsenic through their drinking water. In this study, the effect of arsenic exposure and arsenical skin lesion status on genome-wide gene expression patterns was evaluated using RNA from peripheral blood lymphocytes of individuals selected from the Health Effects of Arsenic Longitudinal Study. Affymetrix HG-U133A GeneChip (Affymetrix, Santa Clara, CA) arrays were used to measure the expression of f22,000 transcripts. Our primary statistical analysis involved identifying differentially expressed genes between participants with and without arsenical skin lesions based on the significance analysis of microarrays statistic with an a priori defined 1% false discovery rate to minimize false positives. To better characterize differential expression, we also conducted Gene Ontology and pathway comparisons in addition to the gene-specific analyses. Fourhundred sixty-eight genes were differentially expressed between these two groups, from which 312 differentially expressed genes were identified by restricting the analysis to female never-smokers. We also explored possible differential gene expression by arsenic exposure levels among individuals without manifest arsenical skin lesions; however, no differentially expressed genes could be identified from this comparison. Our findings show that microarray-based gene expression analysis is a powerful method to characterize the molecular profile of arsenic exposure and arsenic-induced diseases. Genes identified from this analysis may provide insights into the underlying processes of arsenic-induced disease and represent potential targets for chemoprevention studies to reduce arsenicinduced skin cancer in this population.

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“…The significance of the loss of MnSOD expression in cancer cells is underscored by the results of studies that demonstrated MnSOD overexpression can attenuate their malignant phenotypes. [5][6][7] Collectively, these findings have led to the hypothesis that that MnSOD functions as a type of tumor suppressor gene. 8 Breast carcinoma cells and primary tumors generally have lower MnSOD expression and activity than their normal nontumorgenic counterparts.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Regulation of Manganese Superoxide Dismutase Expression in Human Breast Cancer Cells

Hitchler¹,

Wikainapakul²,

Yu³

et al. 2006

Epigenetics

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Malignant breast cancer cells often exhibit lower expression and activity of manganese superoxide dismutase (MnSOD) than their normal cell counterparts; however, the mechanism(s) responsible for this change remains unclear. We examined whether SOD2, the gene encoding MnSOD, was epigenetically repressed in breast cancer cell lines by DNA methylation and histone acetylation. RT-PCR analysis of SOD2 mRNA showed the nontumorigenic breast epithelial cell line MCF-10A to have two to three fold higher expression levels than either UACC-893 or MDA-MB-435 breast carcinoma cells. Analysis of a region in the SOD2 promoter by sodium bisulfite genomic sequencing demonstrated significantly higher levels of CpG methylation in both human breast carcinoma cell lines assessed than in MCF-10A cells. CREB binding in vitro to a cognate site derived from this region was repressed by DNA methylation, and CREB binding to the 5' regulatory region of the SOD2 gene in vivo as determined by ChIP was significantly lower in breast carcinoma cells than in MCF-10A. Increased cytosine methylation was also accompanied by a significant decrease in the level of acetylated histones in the same region of the SOD2 promoter. Finally, a causal link between cytosine methylation and transcriptional repression was established by increasing MnSOD mRNA, protein and activity in breast carcinoma cells using the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine. These findings indicate that epigenetic silencing of SOD2 constitutes one mechanism leading to the decreased expression of MnSOD observed in many breast cancers.

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Inhibition of Cell Growth by Overexpression of Manganese Superoxide Dismutase (MnSOD) in Human Pancreatic Carcinoma

Cited by 71 publications

References 17 publications

Maintenance of Manganese Superoxide Dismutase (SOD2)-Mediated Delayed Radioprotection Induced by Repeated Administration of the Free Thiol Form of Amifostine

Maintenance of Manganese Superoxide Dismutase (SOD2)-Mediated Delayed Radioprotection Induced by Repeated Administration of the Free Thiol Form of Amifostine

Gene Expression Profiles in Peripheral Lymphocytes by Arsenic Exposure and Skin Lesion Status in a Bangladeshi Population

Epigenetic Regulation of Manganese Superoxide Dismutase Expression in Human Breast Cancer Cells

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