Gene Summary

Gene:SOD2; superoxide dismutase 2
Summary:This gene is a member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial protein that forms a homotetramer and binds one manganese ion per subunit. This protein binds to the superoxide byproducts of oxidative phosphorylation and converts them to hydrogen peroxide and diatomic oxygen. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 1. [provided by RefSeq, Apr 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:superoxide dismutase [Mn], mitochondrial
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Cell Proliferation
  • Hydrogen Peroxide
  • Lung Cancer
  • Polymorphism
  • Transfection
  • Single Nucleotide Polymorphism
  • Breast Cancer
  • Apoptosis
  • Cohort Studies
  • Glutathione Peroxidase
  • Alleles
  • Antioxidants
  • Catalase
  • Squamous Cell Carcinoma
  • Base Sequence
  • Skin Aging
  • Gene Expression Profiling
  • Cell Survival
  • Prostate Cancer
  • Biomarkers, Tumor
  • Enzymologic Gene Expression Regulation
  • Genetic Association Studies
  • Signal Transduction
  • Statistics as Topic
  • Chromosome 6
  • United Kingdom
  • Mitochondria
  • Risk Factors
  • Genetic Variation
  • Messenger RNA
  • Genotype
  • Cancer Gene Expression Regulation
  • bcl-X Protein
  • Genetic Predisposition
  • Odds Ratio
  • Case-Control Studies
  • Staging
  • Gene Expression
  • Oxidative Stress
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SOD2 (cancer-related)

Li X, Chen Y, Zhao J, et al.
The Specific Inhibition of SOD1 Selectively Promotes Apoptosis of Cancer Cells via Regulation of the ROS Signaling Network.
Oxid Med Cell Longev. 2019; 2019:9706792 [PubMed] Free Access to Full Article Related Publications
Multiple signaling pathways including ERK, PI3K-Akt, and NF-

Fan JJ, Hsu WH, Hung HH, et al.
Reduction in MnSOD promotes the migration and invasion of squamous carcinoma cells.
Int J Oncol. 2019; 54(5):1639-1650 [PubMed] Free Access to Full Article Related Publications
Reactive oxygen species (ROS) homeostasis is maintained at a higher level in cancer cells, which promotes tumorigenesis. Oxidative stress induced by anticancer drugs may further increase ROS to promote apoptosis, but can also enhance the metastasis of cancer cells. The effects of ROS homeostasis on cancer cells remain to be fully elucidated. In the present study, the effect of a reduction in manganese superoxide dismutase (MnSOD) on the migration and invasion of A431 cells was investigated. Our previous micro‑assay data revealed that the mRNA expression of MnSOD was higher in the invasive A431‑III cell line compared with that in the parental A431 cell line (A431‑P). In the present study, high protein levels of MnSOD and H2O2 production were observed in A431‑III cells; however, catalase protein levels were significantly lower in A431‑III cells compared with those in the A431‑P cell line. The knockdown of MnSOD increased H2O2 levels, enzyme activity, the mRNA levels of matrix metalloproteinase‑1, ‑2 and ‑9, and the migratory and invasive abilities of the cells. Inducing a reduction in H2O2 using diphenyleneiodonium (DPI) and N‑acetyl‑l‑cysteine decreased the migratory abilities of the cell lines, and DPI attenuated the migratory ability that had been increased by MnSOD small interfering RNA knockdown. Luteolin (Lu) and quercetin (Qu) increased the expression of catalase and reduced H2O2 levels, but without an observed change in the protein levels of MnSOD. Taken together, these data suggest that reduced MnSOD may induce ROS imbalance in cells and promote the metastatic ability of cancer cells. Lu and Qu may attenuate these processes and may be promising potential anticancer agents.

Zhang L, Guo Y, Wang H, et al.
Edaravone reduces Aβ-induced oxidative damage in SH-SY5Y cells by activating the Nrf2/ARE signaling pathway.
Life Sci. 2019; 221:259-266 [PubMed] Related Publications
AIMS: Edaravone potentially alleviates cognitive deficits in a mouse model of Alzheimer's disease (AD). However, the mechanism of edaravone in suppressing AD progression remains unclear. We aim to investigate the mechanism of edaravone in suppressing oxidative stress-mediated AD progression in vitro.
MAIN METHODS: Human neuroblastoma SH-SY5Y cells were pretreated with different concentrations of edaravone prior to the induction by Aβ
KEY FINDINGS: The results showed that apoptosis and reactive oxygen species levels significantly increased in Aβ
SIGNIFICANCE: Activation of the Nrf2/ARE signaling pathway may underlie the protective effects of edaravone against the oxidative damage associated with Alzheimer's disease.

Lee HJ, Bahr JM, Bitterman P, et al.
Polycystic Ovarian Condition May Be a Risk Factor for Ovarian Tumor Development in the Laying Hen Model of Spontaneous Ovarian Cancer.
J Immunol Res. 2018; 2018:2590910 [PubMed] Free Access to Full Article Related Publications
Chronic inflammation and long-standing oxidative stress are potential predisposing factors for developing malignancies, including ovarian cancer (OVCA). Information on the association of ovarian chronic abnormal conditions, including polycystic ovarian syndrome (PCOS), with the development of OVCA is unknown. The goal of this study was to examine if polycystic ovarian conditions are associated with OVCA development. In the exploratory study, 3-4-year-old laying hens were randomly selected and examined for the presence of polycystic ovaries with cancer (PCOC). In the prospective study, hens were monitored by ultrasound scanning to detect the incidence of a polycystic ovaries and subsequent development of OVCA. Tissues from normal ovaries and PCOC were examined for macrophage infiltration, expression of interleukin-16, and superoxide dismutase 2. The exploratory study detected spontaneous PCOC at early and late stages in hens. PCOC in hens were accompanied with influx of macrophages (17.33 ± 2.26 in PCOC at the early stage and 24.24 ± 2.5 in PCOC at the late stage in 20 mm

DE Moura CFG, Soares GR, Ribeiro FAP, et al.
Evaluation of the Chemopreventive Activity of Grape Skin Extract Using Medium-term Oral Carcinogenesis Assay Induced by 4-Nitroquinoline 1-Oxide.
Anticancer Res. 2019; 39(1):177-182 [PubMed] Related Publications
BACKGROUND/AIM: The aim of this study was to evaluate the chemoprotective potential of grape skin extract following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide (4NQO).
MATERIALS AND METHODS: Male Wistar rats were distributed into four groups (n=5, per group): Control Group: free access to commercial diet and drinking water for 12 weeks; 4NQO Group: received 4NQO diluted in drinking water daily, for 12 weeks; Grape Skin Extract Group: free access to water and received grape skin extract incorporated with diet for 12 weeks; 4NQO + Grape Skin Extract Group: received 4NQO in drinking water daily and grape extract incorporated with diet for 12 weeks.
RESULTS: Animals treated with grape skin extract revealed a significant reduction in epithelial dysplasia. Also, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and ki-67 immunoexpression was reduced in animals treated with grape skin extract. Western blot analysis showed a significant decrease of p-NFκB p50 and MyD88 protein expression in the groups treated with grape skin extract. Copper-zinc superoxide dismutase, manganese superoxide dismutase, and catalase gene expression did not present any statistically significant differences (p>0.05).
CONCLUSION: Grape skin extract displayed chemopreventive activity in oral carcinogenesis assays as depicted by its antioxidant, anti-proliferative and anti-inflammatory properties.

Mahbouli S, Talvas J, der Vartanian A, et al.
Activation of antioxidant defences of human mammary epithelial cells under leptin depend on neoplastic state.
BMC Cancer. 2018; 18(1):1264 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Obesity is associated with oxidative stress, a major factor in carcinogenesis, and with high leptin concentration. The aim of this study was to determine the effects of leptin on the antioxidant response in three human mammary epithelial cells each presenting a different neoplastic status: healthy human mammary epithelial cells (HMEC), oestrogen-receptor positive MCF-7 cells and triple-negative MDA-MB-231 cells.
METHODS: This in vitro kinetic study characterized the cell antioxidant response after 1, 6 and 24 h in the presence of leptin (10 or 100 ng/ml).The antioxidant response was defined in terms of cell glutathione content, gene expression and catalytic activity of antioxidant enzymes (i.e. glutathione peroxidase 1 (Gpx1), glutathione reductase (GR), glutathione S transferase (GST), heme-oxygenase 1 (HO-1) and cyclooxygenase-2 (COX-2)). Oxidative stress occurrence was assessed by lipid hydro peroxide (HPLIP) and isoprostane concentrations in culture media at 24 h.
RESULTS: At both concentrations used, leptin induced ROS production in all cell models, contributing to various antioxidant responses linked to neoplastic cell status. HMEC developed a highly inducible antioxidant response based on antioxidant enzyme activation and an increase in cell GSH content at 10 ng/ml of leptin. However, at 100 ng/ml of leptin, activation of antioxidant response was lower. Conversely, in tumour cells, MCF-7 and MDA-MB-231, leptin did not induce an efficient antioxidant response, at either concentration, resulting in an increase of lipid peroxidation products.
CONCLUSIONS: Leptin can modulate the oxidative status of mammary epithelial cells differently according to their neoplastic state. These novel results shed light on oxidative status changes in mammary cells in the presence of leptin.

Hughes DJ, Kunická T, Schomburg L, et al.
Expression of Selenoprotein Genes and Association with Selenium Status in Colorectal Adenoma and Colorectal Cancer.
Nutrients. 2018; 10(11) [PubMed] Free Access to Full Article Related Publications
Dietary selenium (Se) intake is essential for synthesizing selenoproteins that are important in countering oxidative and inflammatory processes linked to colorectal carcinogenesis. However, there is limited knowledge on the selenoprotein expression in colorectal adenoma (CRA) and colorectal cancer (CRC) patients, or the interaction with Se status levels. We studied the expression of seventeen Se pathway genes (including fifteen of the twenty-five human selenoproteins) in RNA extracted from disease-normal colorectal tissue pairs, in the discovery phase of sixty-two CRA/CRC patients from Ireland and a validation cohort of a hundred and five CRC patients from the Czech Republic. Differences in transcript levels between the disease and paired control mucosa were assessed by the Mann-Whitney U-test.

Flórido A, Saraiva N, Cerqueira S, et al.
The manganese(III) porphyrin MnTnHex-2-PyP
Redox Biol. 2019; 20:367-378 [PubMed] Free Access to Full Article Related Publications
Manganese(III) porphyrins (MnPs) are superoxide dismutase (SOD) mimics with demonstrated beneficial effects in cancer treatment in combination with chemo- and radiotherapy regimens. Despite the ongoing clinical trials, little is known about the effect of MnPs on metastasis, being therefore essential to understand how MnPs affect this process. In the present work, the impact of the MnP MnTnHex-2-PyP

Ahamed M, Akhtar MJ, Khan MAM, et al.
Oxidative stress mediated cytotoxicity and apoptosis response of bismuth oxide (Bi
Chemosphere. 2019; 216:823-831 [PubMed] Related Publications
Bismuth oxide nanoparticles (Bi

Fu Z, Cao X, Yang Y, et al.
Upregulation of FoxM1 by MnSOD Overexpression Contributes to Cancer Stem-Like Cell Characteristics in the Lung Cancer H460 Cell Line.
Technol Cancer Res Treat. 2018; 17:1533033818789635 [PubMed] Free Access to Full Article Related Publications
Manganese superoxide dismutase promotes migration and invasion in lung cancer cells via upregulation of the transcription factor forkhead box M1. Here, we assessed whether upregulation of forkhead box M1 by manganese superoxide dismutase overexpression mediates the acquisition of cancer stem-like cell characteristics in non-small cell lung cancer H460 cells. The second-generation spheroids from H460 cells were used as lung cancer stem-like cells. The levels of manganese superoxide dismutase, forkhead box M1, stemness markers (CD133, CD44, and ALDH1), and transcription factors (Bmi1, Nanog, and Sox2) were analyzed by Western blot. Sphere formation in vitro and carcinogenicity of lung cancer stem-like cells were evaluated by spheroid formation assay and limited dilution xenograft assays. Knockdown or overexpression of manganese superoxide dismutase or/and forkhead box M1 by transduction with short hairpin RNA(shRNA) or complementary DNA were performed for mechanistic studies. We showed that manganese superoxide dismutase and forkhead box M1 amounts as well as the expression levels of stemness markers and transcription factors sphere formation in vitro, and carcinogenicity of lung cancer stem-like cells were higher than in monolayer cells. Lung cancer stem-like cells transduced with manganese superoxide dismutase shRNA or FoxM1 shRNA exhibited decreased sphere formation and lower amounts of stemness markers and transcription factors. Overexpression of manganese superoxide dismutase or FoxM1 in H460 cells resulted in elevated sphere formation rates and protein levels of stemness markers and transcription factors. Meanwhile, manganese superoxide dismutase knockdown or overexpression accordingly altered forkhead box M1 levels. However, forkhead box M1 knockdown or overexpression had no effect on manganese superoxide dismutase levels but inhibited or promoted lung cancer stem-like cell functions. Interestingly, forkhead box M1 overexpression alleviated the inhibitory effects of manganese superoxide dismutase knockdown in lung cancer stem-like cells. In a panel of non-small cell lung cancer cells, including H441, H1299, and H358 cells, compared to the respective monolayer counterparts, the expression levels of manganese superoxide dismutase and forkhead box M1 were elevated in the corresponding spheroids. These findings revealed the role of forkhead box M1 upregulation by manganese superoxide dismutase overexpression in maintaining lung cancer stem-like cell properties. Therefore, inhibition of forkhead box M1 upregulation by manganese superoxide dismutase overexpression may represent an effective therapeutic strategy for non-small cell lung cancer.

Sharma P, Kumar S
Metformin inhibits human breast cancer cell growth by promoting apoptosis via a ROS-independent pathway involving mitochondrial dysfunction: pivotal role of superoxide dismutase (SOD).
Cell Oncol (Dordr). 2018; 41(6):637-650 [PubMed] Related Publications
PURPOSE: Despite a growing body of evidence indicating a potential efficacy of the anti-diabetic metformin as anti-cancer agent, the exact mechanism underlying this efficacy has remained largely unknown. Here, we aimed at assessing putative mechanisms associated with the ability of metformin to reduce the proliferation and migration of breast cancer cells.
METHODS: A battery of in vitro assays including MTT, colony formation, NBT and scratch wound healing assays were performed to assess the viability, proliferation, anti-oxidative potential and migration of breast cancer-derived MCF-7, MDA-MB-231 and T47D cells, respectively. Reactive oxygen species (ROS) assays along with fluorescence microscopy were used to assess apoptotic parameters. Quantification of SOD, Bcl-2, Bax, MMPs, miR-21 and miR-155 expression was performed using qRT-PCR.
RESULTS: We found that metformin inhibited the growth, proliferation and clonogenic potential of the breast cancer-derived cells tested. ROS levels were found to be significantly reduced by metformin and, concomitantly, superoxide dismutase (SOD) isoforms were found to be upregulated. Mitochondrial dysfunction was observed in metformin treated cells, indicating apoptosis. In metastatic MDA-MB-231 cells, migration was found to be suppressed by metformin through deregulation of the matrix metalloproteinases MMP-2 and MMP-9. The oncogenic microRNAs miR-21 and miR-155 were found to be downregulated by metformin, which may be correlated with the suppression of cell proliferation and/or migration.
CONCLUSIONS: Our data indicate that metformin may play a pivotal role in modulating the anti-oxidant system, including the SOD machinery, in breast cancer-derived cells. Our observations were validated by in silico analyses, indicating a close interaction between SOD and metformin. We also found that metformin may inhibit breast cancer-derived cell proliferation through apoptosis induction via the mitochondrial pathway. Finally, we found that metformin may modulate the pro-apoptotic Bax, anti-apoptotic Bcl-2, MMP-2, MMP-9, miR-21 and miR-155 expression levels. These findings may be instrumental for the clinical management and/or (targeted) treatment of breast cancer.

Zhang Y, Xu Z, Ding J, et al.
HZ08 suppresses RelB-activated MnSOD expression and enhances Radiosensitivity of prostate Cancer cells.
J Exp Clin Cancer Res. 2018; 37(1):174 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The development of radioresistance is one of main causes for therapeutic failure of prostate cancer (PCa). The present study aims to investigate the function and the related mechanism by which HZ08 sensitizes radiotherapeutic efficiency to treat aggressive PCa cells.
METHODS: PCa cells were pretreated with HZ08 (6,7-dimethoxy-1-(3,4-dimethoxy) benzyl-2-(N-n-octyl-N'-cyano) guanyl-1,2,3,4-tetrahydroisoquinoline) and followed by ionizing radiation (IR) treatment. Cytotoxicity in the treated cells was analyzed to assess the radiosensitization capacity of HZ08 by flow cytometry, MTT and colony survival assays. The cellular levels of reactive oxygen species (ROS) and oxygen consumption rates (OCR) were measured using specific ROS detection probes and a Seahorse XF96 Analyzer, respectively. RelB binding to the NF-κB intronic enhancer region of the human SOD2 gene was determined using a ChIP assay. The levels of phosphorylation of PI3K, Akt and IKKα were quantified and further confirmed using a PI3K inhibitor. Finally, the synergistic effect of HZ08 on radiosensitization of PCa cells was validated using a mouse xenograft tumor model.
RESULTS: HZ08 enhanced radiosensitivity of PCa cells through increasing ROS and declining mitochondrial respiration due to suppression of mitochondrial antioxidant enzyme MnSOD. Mechanistically, HZ08 appeared to inhibit PI3K/Akt/IKKα signaling axis, resulting in transcriptional repression of MnSOD expression by preventing RelB nuclear translocation.
CONCLUSIONS: HZ08 can serve as a useful radiosensitizing agent to improve radiotherapy for treating aggressive PCa cells with high level of constitutive RelB. The present study suggests a promising approach for enhancing radiotherapeutic efficiency to treat advanced PCa by inhibiting antioxidant defense function.

van Ooijen H, Hornsveld M, Dam-de Veen C, et al.
Assessment of Functional Phosphatidylinositol 3-Kinase Pathway Activity in Cancer Tissue Using Forkhead Box-O Target Gene Expression in a Knowledge-Based Computational Model.
Am J Pathol. 2018; 188(9):1956-1972 [PubMed] Related Publications
The phosphatidylinositol 3-kinase (PI3K) pathway is commonly activated in cancer. Tumors are potentially sensitive to PI3K pathway inhibitors, but reliable diagnostic tests that assess functional PI3K activity are lacking. Because PI3K pathway activity negatively regulates forkhead box-O (FOXO) transcription factor activity, FOXO target gene expression is inversely correlated with PI3K activity. A knowledge-based Bayesian computational model was developed to infer PI3K activity in cancer tissue samples from FOXO target gene mRNA levels and validated in cancer cell lines treated with PI3K inhibitors. However, applied to patient tissue samples, FOXO was often active in cancer types with expected active PI3K. SOD2 was differentially expressed between FOXO-active healthy and cancer tissue samples, indicating that cancer-associated cellular oxidative stress alternatively activated FOXO. To enable correct interpretation of active FOXO in cancer tissue, threshold levels for normal SOD2 expression in healthy tissue were defined above which FOXO activity is oxidative stress induced and below which PI3K regulated. In slow-growing luminal A breast cancer and low Gleason score prostate cancer, FOXO was active in a PI3K-regulated manner, indicating inactive PI3K. In aggressive luminal B, HER2, and basal breast cancer, FOXO was increasingly inactive or actively induced by oxidative stress, indicating PI3K activity. We provide a decision tree that facilitates functional PI3K pathway activity assessment in tissue samples from patients with cancer for therapy response prediction and prognosis.

Gaikwad S, Chakraborty A, Salwe S, et al.
Juglone-ascorbic acid synergy inhibits metastasis and induces apoptotic cell death in poorly differentiated thyroid carcinoma by perturbing SOD and catalase activities.
J Biochem Mol Toxicol. 2018; 32(9):e22176 [PubMed] Related Publications
Anaplastic thyroid carcinoma (ATC) requires more innovative approaches as the current regimes for therapy are inadequate, also most anticancer drugs cause general suppression of physiological functions. However, therapy with limited nontarget tissue damage is desirable. In the present study, we show prooxidant ability of ascorbic acid, which enhances cytotoxicity induced by juglone. We decipher that juglone-ascorbate combination induces reactive oxygen species-mediated apoptosis leading to cell death in ARO cell line originated from ATC. This combination also affects enzyme activity of catalase, glutathione reductase, and superoxide dismutase destabilizing redox balance in cell and thereby making juglone effective at a lower dose. We also show that juglone-ascorbate combination suppresses cell migration, invasion, and expression of tumor-promoting, and angiogenic genes in ARO cell line, thereby disrupting epithelial-mesenchymal transition ability of the cells. Overall, we show that ascorbic acid increases cytotoxic potency of juglone through redox cycling when used in synergy.

Qiu J, Zhang H, Wang Z
Auricularia auriculajudae polysaccharide-cisplatin complexes conjugated with folic acid as new tumor targeting agents.
Int J Biol Macromol. 2018; 120(Pt A):966-974 [PubMed] Related Publications
The Auricularia auriculajudae polysaccharide-cisplatin complex (AAP-CDDP) was synthesized and characterized. The drug release, hemocompatibility, anti-tumor activity, and targeting ability of the complex were studied. The results of cell assay showed that the FA-AAP-CDDP complex showed better anti-tumor activity (IC

Iplik ES, Ertugrul B, Candan G, et al.
ROS related enzyme levels and its association to molecular signaling pathway in the development of head and neck cancer.
Cell Mol Biol (Noisy-le-grand). 2018; 64(7):24-29 [PubMed] Related Publications
Given the prevalence and annual incidence of cancer, head and neck cancer is affecting more than 600,000 people each year. In this research, it was decided to investigate that which genes are involved and how MPO, NQO1, SOD2 enzyme levels effective to develop of head and neck cancer and for the first time at the tissue level. 35 tumor tissues in all head and neck anatomy and their surrounding tissue (70 in total) were enclosed the research that received surgery. Determination of the apoptosis genes expression levels (Mtch1, Akt1, Caspase3, Caspase9, Bcl2, Mdm2, mTOR) were determined by RT-PCR techniques and the same patients' sample used for ROS associated oxidant-antioxidant system by using MPO, NQO1, SOD2 enzyme levels using ELISA method. According to statistical results, caspase 9 gene was found statistically high expressed in early stage in contrast to late stage (p=0,013). Level of SOD2, NQO1 and MPO was determined and only MPO level was found significantly important on tumor tissues p=0,008).  Specially, our findings for high expression of Cas9 on early stage were thought to be the target for treatment with its well-known initiator role of the apoptosis. Our results suggest that the higher level of MPO in tumor tissues and indicates that it has some role on pathology of head and neck cancers. We believe that, our research will lead the proposal in-vivo studies and will open new areas on therapeutic targets.

Zhao Z, Lu J, Qu H, et al.
Evaluation and prognostic significance of manganese superoxide dismutase in clear cell renal cell carcinoma.
Hum Pathol. 2018; 80:87-93 [PubMed] Related Publications
The antioxidant enzyme manganese superoxide dismutase (MnSOD) is up-regulated in renal cell carcinoma (RCC) and has been implicated in multiple stages of RCC tumorigenesis and progression. However, the prognostic significance of MnSOD in RCC has not been fully elucidated. This study aimed to investigate the expression profile of MnSOD in clear cell RCC (ccRCC) tissues and evaluate the clinical significance of this enzyme in ccRCC patients. MnSOD mRNA was assessed in 42 ccRCC and 33 normal kidney tissues using the Oncomine database, and its protein was detected in 145 ccRCCs and 3 normal tissues by immunohistochemistry staining. The Oncomine database confirmed higher MnSOD mRNA expression in ccRCC than in normal tissues, and immunohistochemistry analysis revealed that MnSOD protein expression was inversely associated with pathologic grade, clinical stage, tumor size, M status, and cancer-specific survival. In addition, univariate survival analysis demonstrated that high-grade, late-stage, large tumors, stage M

Yoshida T, Kageyama S, Isono T, et al.
Superoxide dismutase 2 expression can predict prognosis of renal cell carcinoma patients.
Cancer Biomark. 2018; 22(4):755-761 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: Renal cell carcinoma (RCC) is the urological malignancy with the highest mortality rate and is increasing in incidence. The prognostic and predictive biomarkers are highly desired. This study aims to investigate the significance of superoxide dismutase 2 (SOD2) as a clinical biomarker in patients with renal cell carcinomas.
METHODS: A cohort of 97 patients with RCC was analyzed retrospectively using various clinical parameters and SOD2 expression by immunohistochemistry.
RESULTS: Cases with stronger SOD2 positivity of the tumor in comparison to the adjacent normal renal tubule by immunohistochemistry were categorized as high SOD2 and were associated with worse overall survivals (p= 0.005). In particular, in cases with metastatic RCC, high SOD2 expression in the tumors was significantly associated with a worse overall survival (p= 0.001), and the maximum critical risk. Treatment with current molecular targeting therapies did not improve the prognoses of cases with metastatic or recurrent RCC.
CONCLUSIONS: High SOD2 expression can be predictive of a poor clinical outcome and be clinically useful in the follow-up of metastatic RCC. Therapeutics for metastatic RCCs require further improvement, such as supplementary administration of agents targeting mitochondrial SOD2.

Hassani S, Ghaffari P, Chahardouli B, et al.
Disulfiram/copper causes ROS levels alteration, cell cycle inhibition, and apoptosis in acute myeloid leukaemia cell lines with modulation in the expression of related genes.
Biomed Pharmacother. 2018; 99:561-569 [PubMed] Related Publications
The majority of acute myeloid leukaemia (AML) patients will die from their disease or therapy-related complications. There is an inevitable need to improve the survival of AML patients. Previous studies show that disulfiram (DSF), an anti-alcoholism drug with a low toxicity profile, demonstrates anticancer behaviors. Here, we evaluated the cytotoxicity and mechanistic action of DSF on the AML cell lines KG-1, NB4, and U937. The microculture tetrazolium test revealed that DSF alone or in combination with copper (Cu) is highly toxic to the AML cells at concentrations lower than those achievable in the clinical setting, with Cu increasing the DSF-induced inhibition of metabolic activity. Flow cytometric analysis and QRT-PCR indicated that in the two cell lines, NB4 and U-937, DSF/Cu increased reactive oxygen species (ROS) levels in association with the induction of superoxide dismutase 2 (SOD2) expression and suppression of catalase (CAT). In the KG-1 cell line, DSF/Cu reduced the ROS levels in agreement with the induction of CAT expression. The cell cycle and apoptosis assessment by flow cytometry demonstrated that DSF/Cu induced G0/G1 cell cycle arrest and apoptosis. These were associated with the increased expression of FOXO tumor suppressors, decreased expression of the MYC oncogene and the modulation of their known target genes related to the cell cycle and apoptosis. Therefore, DSF/Cu caused the disturbance of the ROS balance, cell cycle arrest and apoptosis in AML cells in coordination with the modulation in expression of their related genes. These results propose the possible use of DSF in AML therapies.

Li S, Fu L, Tian T, et al.
Disrupting SOD1 activity inhibits cell growth and enhances lipid accumulation in nasopharyngeal carcinoma.
Cell Commun Signal. 2018; 16(1):28 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: SOD1 is an abundant enzyme that has been studied as a regulator of the antioxidant defence system, and this enzyme is well known for catalyzing the dismutation of superoxide into hydrogen peroxide. However the SOD1 in the progress of NPC and underlying mechanisms remain unclear.
METHODS: In NPC tissue samples, SOD1 protein levels were measured by Western blot and immunohistochemical (IHC) staining. mRNA levels and SOD1 activity were monitored by qRT-PCR and SOD activity kit, respectively. Kaplan-Meier survival analysis was performed to explore the relationship between SOD1 expression and prognosis of NPC. The biological effects of SOD1 were investigated both in vitro by CCK-8, clonogenicity and apoptosis assays and in vivo by a xenograft mice model. Western blotting, ROS assay and triglyceride assays were applied to investigate the underlying molecular mechanism of pro-survival role of SOD1 in NPC.
RESULTS: We observed a significant upregulation of SOD1 in NPC tissue and high SOD1 expression is a predictor of poor prognosis and is correlated with poor outcome. We confirmed the pro-survival role of SOD1 both in vitro and in vivo. We demonstrated that these mechanisms of SOD1 partly exist to maintain low levels of the superoxide anion and to avoid the accumulation of lipid droplets via enhanced CPT1A-mediated fatty acid oxidation.
CONCLUSIONS: The results of this study indicate that SOD1 is a potential prognostic biomarker and a promising target for NPC therapy.

Pedro NF, Biselli JM, Maniglia JV, et al.
Candidate Biomarkers for Oral Squamous Cell Carcinoma: Differential Expression of Oxidative Stress-Related Genes
Asian Pac J Cancer Prev. 2018; 19(5):1343-1349 [PubMed] Free Access to Full Article Related Publications
Background: Alteration in the biotransformation of exogenous compounds can result in production of reactive oxygen species (ROS), which can predispose cells to malignant transformation in the head and neck. This study aimed to evaluate the expression of genes involved in antioxidant metabolism in the oral squamous cell carcinoma (OSCC). Methods: The expression of eighty-four genes was evaluated in OSCC and non-tumor tissues by quantitative real-time polymerase chain reaction using the TaqMan Gene Expression Array. The biological mechanisms related to the differentially expressed genes were investigated using Gene – NCBI, KEGG, UNIPROT and REACTOME databases. Results: Twenty-one genes encoding enzymes involved in antioxidant metabolism were differentially expressed in the OSCC case. Four genes (ATOX1, PRDX4, PRNP, and SOD2) were up-regulated, and seventeen (ALOX12, CAT, CSDE1, DHCR24, DUOX1, DUOX2, EPHX2, GLRX2, GPX3, GSR, GSTZ1, MGST3, PRDX1, OXR1, OXSR1, SOD1, and SOD3) were down-regulated. We identified 14 possible novel biomarkers for OSCC. The differentially expressed genes appeared related to important biological processes involved in carcinogenesis, such as inflammation, angiogenesis, apoptosis, genomic instability, invasion, survival, and cell proliferation. Conclusions: Our study identified novel biomarkers which might warrant further investigation regarding OSCC pathogenesis since the altered expression in the genes can modulate biological processes related to oxidative stress and predispose cells to malignant transformation in the oral cavity.

Cheng CC, Shi LH, Wang XJ, et al.
Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066.
Int J Oncol. 2018; 53(1):339-348 [PubMed] Related Publications
Doxorubicin (Dox) is widely used in the treatment of triple-negative breast cancer cells (TNBCs), however resistance limits its effectiveness. Cancer stem cells (CSCs) are associated with Dox resistance in MCF-7 estrogen receptor positive breast cancer cells. Signal transducer and activator of transcription 3 (Stat3) may functionally shift non-CSCs towards CSCs. However, whether Stat3 drives the formation of CSCs during the development of resistance in TNBC, and whether a Stat3 inhibitor reverses CSC-mediated Dox resistance, remains to be elucidated. In the present study, human MDA-MB-468 and murine 4T1 mammary carcinoma cell lines with the typical characteristics of TNBCs, were compared with estrogen receptor-positive MCF-7 cells as a model system. The MTT assay was used to detect cytotoxicity of Dox. In addition, the expression levels of CSC-specific markers and transcriptional factors were measured by western blotting, immunofluorescence staining and flow cytometry. The mammosphere formation assay was used to detect stem cell activity. Under long-term continuous treatment with Dox at a low concentration, TNBC cultures not only exhibited a drug-resistant phenotype, but also showed CSC properties. These Dox-resistant TNBC cells showed activation of Stat3 and high expression levels of pluripotency transcription factors octamer-binding transcription factor-4 (Oct-4) and c-Myc, which was different from the high expression of superoxide dismutase 2 (Sox2) in Dox-resistant MCF-7 cells. WP1066 inhibited the phosphorylation of Stat3, and decreased the expression of Oct-4 and c-Myc, leading to a reduction in the CD44-positive cell population, and restoring the sensitivity of the cells to Dox. Taken together, a novel signal circuit of Stat3/Oct-4/c-Myc was identified for regulating stemness-mediated Dox resistance in TNBC. The Stat3 inhibitor WP1066 was able to overcome the resistance to Dox through decreasing the enrichment of CSCs, highlighting the therapeutic potential of WP1066 as a novel sensitizer of Dox-resistant TNBC.

Li L, Zhong Y, Ma Z, et al.
Methyl ferulic acid exerts anti-apoptotic effects on L-02 cells via the ROS-mediated signaling pathway.
Int J Oncol. 2018; 53(1):225-236 [PubMed] Related Publications
The present study aimed to investigate the anti-apoptotic effects of methyl ferulic acid (MFA) on L-02 cell apoptosis induced by ethanol, and to elucidate the possible underlying mechanisms. L-02 cells were examined after being soaked in ethanol (400 mM) to allow the ethanol to permeate into the cells for 24 h. Cell survival was measured by MTT assay. Cell apoptosis was assessed by both flow cytometry and single-stranded DNA assays. Intracellular reactive oxygen species (ROS) production was determined using the 2',7'-dichlorofluorescein-diacetate dye. The protein expression levels of p38, p-p38, JNK, p-JNK, NADPH oxidase 4 (NOX4), p22, Bax and Bcl-2 were measured by western blot analysis. The mRNA expression levels of NOX4 and p22 were measured by RT-PCR. It was identified that MFA markedly suppressed the ethanol-induced apoptosis and necrosis of L-02 cells. In addition, MFA decreased the expression levels of superoxide dismutase, catalase and phospholipid hydroperoxide gluthione peroxidase, and downregulated the levels of Bax/Bcl-2 and the cleaved forms of caspase-3 in a dose- and time-dependent manner. This indicated that MFA attenuated the apoptosis of L-02 cells. MFA also decreased the elevated mRNA and protein expression levels of Nox4 and p22phox, and the production of intracellular ROS triggered by ethanol. Further analysis demonstrated that MFA significantly attenuated the phosphorylation of JNK and p38, which are major components of the mitogen-activated protein kinase (MAPK) pathways. On the whole, the findings of this study demonstrated that MFA attenuated the apoptotic cell death of L-02 cells by reducing the generation of ROS and inactivating the MAPK pathways.

Wang S, Beeghly-Fadiel A, Cai Q, et al.
Gene expression in triple-negative breast cancer in relation to survival.
Breast Cancer Res Treat. 2018; 171(1):199-207 [PubMed] Related Publications
PURPOSE: The identification of biomarkers related to the prognosis of triple-negative breast cancer (TNBC) is critically important for improved understanding of the biology that drives TNBC progression.
METHODS: We evaluated gene expression in total RNA isolated from formalin-fixed paraffin-embedded tumor samples using the NanoString nCounter assay for 469 TNBC cases from the Shanghai Breast Cancer Survival Study. We used Cox regression to quantify Hazard Ratios (HR) and corresponding confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS) in models that included adjustment for breast cancer intrinsic subtype. Of 302 genes in our discovery analysis, 22 were further evaluated in relation to OS among 134 TNBC cases from the Nashville Breast Health Study and the Southern Community Cohort Study; 16 genes were further evaluated in relation to DFS in 335 TNBC cases from four gene expression omnibus datasets. Fixed-effect meta-analysis was used to combine results across data sources.
RESULTS: Twofold higher expression of EOMES (HR 0.90, 95% CI 0.83-0.97), RASGRP1 (HR 0.89, 95% CI 0.82-0.97), and SOD2 (HR 0.80, 95% CI 0.66-0.96) was associated with better OS. Twofold higher expression of EOMES (HR 0.89, 95% CI 0.81-0.97) and RASGRP1 (HR 0.87, 95% CI 0.81-0.95) was also associated with better DFS. On the contrary, a doubling of FA2H (HR 1.14, 95% CI 1.06-1.22) and GSPT1 (HR 1.33, 95% CI 1.14-1.55) expression was associated with shorter DFS.
CONCLUSIONS: We identified five genes (EOMES, FA2H, GSPT1, RASGRP1, and SOD2) that may serve as potential prognostic biomarkers and/or therapeutic targets for TNBC.

Kusaczuk M, Krętowski R, Naumowicz M, et al.
Silica nanoparticle-induced oxidative stress and mitochondrial damage is followed by activation of intrinsic apoptosis pathway in glioblastoma cells.
Int J Nanomedicine. 2018; 13:2279-2294 [PubMed] Free Access to Full Article Related Publications
Introduction: Recently, the focus of oncological research has been on the optimization of therapeutic strategies targeted at malignant diseases. Nanomedicine utilizing silicon dioxide nanoparticles (SiNPs) is one such strategy and is rapidly developing as a promising tool for cancer diagnosis, imaging, and treatment. Nevertheless, little is known about the mechanisms of action of SiNPs in brain tumors.
Materials and methods: Here, we explored the effects of 5-15 nm SiNPs in the human glioblastoma cell line LN229. In this respect, MTT assays, microscopic observations, flow cytometry analyses, and luminescent assays were performed. Moreover, RT-qPCR and Western blot analyses were done to determine gene and protein expressions.
Results: We demonstrated that SiNPs triggered evident cytotoxicity, with microscopic observations of the nuclei, annexin V-fluorescein isothiocyanate/propidium iodide staining, and elevated caspase 3/7 activity, suggesting that SiNPs predominantly induced apoptotic death in LN229 cells. We further showed the occurrence of oxidative stress induced by enhanced reactive oxygen-species generation. This effect was followed by deregulated expression of genes encoding the antioxidant enzymes SOD1, SOD2, and CAT, and impaired mitochondria function. SiNP- induced mitochondrial dysfunction was characterized by membrane-potential collapse, ATP depletion, elevated expression of
Conclusions: Altogether, our data indicate that in LN229 cells, SiNPs evoke cell death via activation of the intrinsic apoptosis pathway and suggest that other aspects of cellular function may also be affected. As such, SiNPs represent a potentially promising agent for facilitating further progress in brain cancer therapy. However, further exploration of SiNP long-term toxicity and molecular effects is necessary prior to their widespread application.

Gonzalez-Menendez P, Hevia D, Alonso-Arias R, et al.
GLUT1 protects prostate cancer cells from glucose deprivation-induced oxidative stress.
Redox Biol. 2018; 17:112-127 [PubMed] Free Access to Full Article Related Publications
Glucose, chief metabolic support for cancer cell survival and growth, is mainly imported into cells by facilitated glucose transporters (GLUTs). The increase in glucose uptake along with tumor progression is due to an increment of facilitative glucose transporters as GLUT1. GLUT1 prevents cell death of cancer cells caused by growth factors deprivation, but there is scarce information about its role on the damage caused by glucose deprivation, which usually occurs within the core of a growing tumor. In prostate cancer (PCa), GLUT1 is found in the most aggressive tumors, and it is regulated by androgens. To study the response of androgen-sensitive and insensitive PCa cells to glucose deprivation and the role of GLUT1 on survival mechanisms, androgen-sensitive LNCaP and castration-resistant LNCaP-R cells were employed. Results demonstrated that glucose deprivation induced a necrotic type of cell death which is prevented by antioxidants. Androgen-sensitive cells show a higher resistance to cell death triggered by glucose deprivation than castration-resistant cells. Glucose removal causes an increment of H

Md Fuzi AA, Omar SZ, Mohamed Z, et al.
High throughput silencing identifies novel genes in endometrioid endometrial cancer.
Taiwan J Obstet Gynecol. 2018; 57(2):217-226 [PubMed] Related Publications
OBJECTIVE: To validate the gene expression profile obtained from the previous microarray analysis and to further study the biological functions of these genes in endometrial cancer. From our previous study, we identified 621 differentially expressed genes in laser-captured microdissected endometrioid endometrial cancer as compared to normal endometrial cells. Among these genes, 146 were significantly up-regulated in endometrial cancer.
MATERIALS AND METHODS: A total of 20 genes were selected from the list of up-regulated genes for the validation assay. The qPCR confirmed that 19 out of the 20 genes were up-regulated in endometrial cancer compared with normal endometrium. RNA interference (RNAi) was used to knockdown the expression of the upregulated genes in ECC-1 and HEC-1A endometrial cancer cell lines and its effect on proliferation, migration and invasion were examined.
RESULTS: Knockdown of MIF, SOD2, HIF1A and SLC7A5 by RNAi significantly decreased the proliferation of ECC-1 cells (p < 0.05). Our results also showed that the knockdown of MIF, SOD2 and SLC7A5 by RNAi significantly decreased the proliferation and migration abilities of HEC-1A cells (p < 0.05). Moreover, the knockdown of SLC38A1 and HIF1A by RNAi resulted in a significant decrease in the proliferation of HEC1A cells (p < 0.05).
CONCLUSION: We have identified the biological roles of SLC38A1, MIF, SOD2, HIF1A and SLC7A5 in endometrial cancer, which opens up the possibility of using the RNAi silencing approach to design therapeutic strategies for treatment of endometrial cancer.

Li S, Yang E, Shen L, et al.
The novel truncated isoform of human manganese superoxide dismutase has a differential role in promoting metastasis of lung cancer cells.
Cell Biol Int. 2018; 42(8):1030-1040 [PubMed] Related Publications
Growing evidences have demonstrated alternative splicing makes great contribution to tumor metastasis since multiple protein isoforms from a single gene that often display different functions in the cell. Human manganese superoxide dismutase (hMnSOD) was revealed dysregulation in progress of tumor metastasis, while the effect of hMnSOD isoforms on metastasis remained unclear. In this study, we showed a novel truncated hMnSOD isoform hMnSOD183, which lacked 39 amino acids compared with hMnSOD222. We expressed two hMnSOD protein isoforms in Escherichia coli, respectively, and found that the MnSOD activity of truncated hMnSOD isoform was especially weaker. In 95-D cells, mRNA levels of hMnSOD variants and MnSOD activity were significantly increased than that in A549 cells. Furthermore, the hMnSODc exhibited lower mRNA level than hMnSODa/b in A549 and 95-D cells. Additionally, the effects of two isoforms were assessed about cell invasion, overexpression of hMnSOD222 but not hMnSOD183 promoted 95-D cells metastasis, and hMnSOD knockdown significantly reduced cells invasive behavior. Overexpression of hMnSOD isoforms also caused changes of metastasis associated proteins, such as up-regulation of MMPs, VEGF and Vimentin and down-regulation of E-cadherin. Moreover, overexpression of hMnSOD183 had weaker effect on metastasis related signaling proteins, such as Akt, JNK and IKKβ, compared to hMnSOD222. In conclusion, our study identified that hMnSOD isoforms induced lung cancer cells invasion through Akt-JNK-IKKβ signaling pathways and the hMnSOD183 isoform played a weaker role than hMnSOD222. Characterization of hMnSOD isoforms is useful for future investigation on metastasis of lung cancer cells.

Bulgurcuoglu Kuran S, Iplik ES, Cakmakoglu B, et al.
Relation of MPO, MnSOD, NQO1 gene variants in endometrial carcinoma in the line of PCR-RFLP methods.
Cell Mol Biol (Noisy-le-grand). 2018; 64(4):78-82 [PubMed] Related Publications
Reactive oxygen species (ROS) have been shown to be responsible for inducing DNA damage leading to mutagenesis, carcinogenesis, and cell death if the capacity of the protective antioxidant system is impaired. Endometrial carcinoma is the primary cancer type in the female genital system. The enhanced cell lipid peroxidation and impaired antioxidant enzyme activities observed in patients with endometrial cancer indicate the potential for oxidative injury to cells and cell membranes in such patients. The aim of the study was to investigate the possible association between gene variants of superoxide dismutase (SOD), myeloperoxidase (MPO), and NADPH quinone oxido reductase (NQO1), and their possible role in endometrial cancer in Turkish patients. According to results, MPO G+ genotype and AG genotype were significantly increased in patients compared with controls (P<0.001). We suggest that the MPO polymorphism might be a risk for endometrial cancer.

Castejón-Griñán M, Herraiz C, Olivares C, et al.
cAMP-independent non-pigmentary actions of variant melanocortin 1 receptor: AKT-mediated activation of protective responses to oxidative DNA damage.
Oncogene. 2018; 37(27):3631-3646 [PubMed] Related Publications
The melanocortin 1 receptor gene (MC1R), a well-established melanoma susceptibility gene, regulates the amount and type of melanin pigments formed within epidermal melanocytes. MC1R variants associated with increased melanoma risk promote the production of photosensitizing pheomelanins as opposed to photoprotective eumelanins. Wild-type (WT) MC1R activates DNA repair and antioxidant defenses in a cAMP-dependent fashion. Since melanoma-associated MC1R variants are hypomorphic in cAMP signaling, these non-pigmentary actions are thought to be defective in MC1R-variant human melanoma cells and epidermal melanocytes, consistent with a higher mutation load in MC1R-variant melanomas. We compared induction of antioxidant enzymes and DNA damage responses in melanocytic cells of defined MC1R genotype. Increased expression of catalase (CAT) and superoxide dismutase (SOD) genes following MC1R activation was cAMP-dependent and required a WT MC1R genotype. Conversely, pretreatment of melanocytic cells with an MC1R agonist before an oxidative challenge with Luperox decreased (i) accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanine, a major product of oxidative DNA damage, (ii) phosphorylation of histone H2AX, a marker of DNA double-strand breaks, and (iii) formation of DNA breaks. These responses were comparable in cells WT for MC1R or harboring hypomorphic MC1R variants without detectable cAMP signaling. In MC1R-variant melanocytic cells, the DNA-protective responses were mediated by AKT. Conversely, in MC1R-WT melanocytic cells, high cAMP production downstream of MC1R blocked AKT activation and was responsible for inducing DNA repair. Accordingly, MC1R activation could promote repair of oxidative DNA damage by a cAMP-dependent pathway downstream of WT receptor, or via AKT in cells of variant MC1R genotype.

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