SOD2

Gene Summary

Gene:SOD2; superoxide dismutase 2
Aliases: IPOB, IPO-B, MNSOD, MVCD6, Mn-SOD
Location:6q25.3
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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:superoxide dismutase [Mn], mitochondrial
Source:NCBIAccessed: 16 March, 2017

Ontology:

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 (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 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)

Wieczorek E, Jablonowski Z, Tomasik B, et al.
Different Gene Expression and Activity Pattern of Antioxidant Enzymes in Bladder Cancer.
Anticancer Res. 2017; 37(2):841-848 [PubMed] Related Publications
The aim of this study was to evaluate the possible role in and contribution of antioxidant enzymes to bladder cancer (BC) etiology and recurrence after transurethral resection (TUR). We enrolled 40 patients with BC who underwent TUR and 100 sex- and age-matched healthy controls. The analysis was performed at diagnosis and recurrence, taking into account the time of recurrence. Gene expression of catalase (CAT), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (SOD2) was determined in peripheral blood leukocytes. The activity of glutathione peroxidase 3 (GPX3) was examined in plasma, and GPX1 and copper-zinc containing superoxide dismutase 1 (SOD1) in erythrocytes. SOD2 and GPX1 expression and GPX1 and SOD1 activity were significantly higher in patients at diagnosis of BC in comparison to controls. In patients who had recurrence earlier than 1 year from TUR, CAT and SOD2 expression was lower (at diagnosis p=0.024 and p=0.434, at recurrence p=0.022 and p=0.010), while the GPX1 and GPX3 activity was higher (at diagnosis p=0.242 and p=0.394, at recurrence p=0.019 and p=0.025) compared to patients with recurrence after 1 year from TUR. This study revealed that the gene expression and activity of the antioxidant enzymes are elevated in blood of patients with BC, although a low expression of CAT might contribute to the recurrence of BC, in early prognosis.

Kimáková P, Solár P, Fecková B, et al.
Photoactivated hypericin increases the expression of SOD-2 and makes MCF-7 cells resistant to photodynamic therapy.
Biomed Pharmacother. 2017; 85:749-755 [PubMed] Related Publications
Photoactivated hypericin increased production of reactive oxygen species in human breast adenocarcinoma MCF-7 as well as in MDA-MB-231 cells 1h after photodynamic therapy. On the other hand, reactive oxygen species dropped 3h after photodynamic therapy with hypericin, but only in MCF-7 cells, whereas in MDA-MB-231 cells remained elevated. The difference in the dynamics of reactive oxygen species after hypericin activation was related to increased activity of SOD-2 in MCF-7 cells compared to MDA-MB-231 cells. Indeed, photodynamic therapy with hypericin significantly increased SOD-2 activity in MCF-7 cells, but only slightly in MDA-MB-231 cells. In this regard, SOD-2 activity correlated well with enhanced both mRNA expression as well as SOD-2 protein level in MCF-7 cells. The role of SOD-2 in the resistance of MCF-7 cells to photodynamic therapy with hypericin was monitored using SOD-2 inhibitor - 2-methoxyestradiol. Interestingly, the combination of photodynamic therapy with hypericin and methoxyestradiol sensitized MCF-7 cells to photodynamic therapy and significantly reduced its clonogenic ability. Furthermore, methoxyestradiol potentiated the activation of caspase 3/7 and apoptosis induced by photodynamic therapy with hypericin.

Ahamed M, Akhtar MJ, Khan MA, et al.
Cobalt iron oxide nanoparticles induce cytotoxicity and regulate the apoptotic genes through ROS in human liver cells (HepG2).
Colloids Surf B Biointerfaces. 2016; 148:665-673 [PubMed] Related Publications
Cobalt iron oxide (CoFe2O4) nanoparticles (CIO NPs) have been one of the most widely explored magnetic NPs because of their excellent chemical stability, mechanical hardness and heat generating potential. However, there is limited information concerning the interaction of CIO NPs with biological systems. In this study, we investigated the reactive oxygen species (ROS) mediated cytotoxicity and apoptotic response of CIO NPs in human liver cells (HepG2). Diameter of crystalline CIO NPs was found to be 23nm with a band gap of 1.97eV. CIO NPs induced cell viability reduction and membrane damage, and degree of induction was dose- and time-dependent. CIO NPs were also found to induce oxidative stress revealed by induction of ROS, depletion of glutathione and lower activity of superoxide dismutase enzyme. Real-time PCR data has shown that mRNA level of tumor suppressor gene p53 and apoptotic genes (bax, CASP3 and CASP9) were higher, while the expression level of anti-apoptotic gene bcl-2 was lower in cells following exposure to CIO NPs. Activity of caspase-3 and caspase-9 enzymes was also higher in CIO NPs exposed cells. Furthermore, co-exposure of N-acetyl-cysteine (ROS scavenger) efficiently abrogated the modulation of apoptotic genes along with the prevention of cytotoxicity caused by CIO NPs. Overall, we observed that CIO NPs induced cytotoxicity and apoptosis in HepG2 cells through ROS via p53 pathway. This study suggests that toxicity mechanisms of CIO NPs should be further investigated in animal models.

Guo H, Zhang N, Liu D, et al.
Inhibitory effect on the proliferation of human heptoma induced by cell-permeable manganese superoxide dismutase.
Biomed Pharmacother. 2016; 83:1379-1386 [PubMed] Related Publications
Mitochondrial antioxidant manganese superoxide dismutase (MnSOD) belongs to a group of genes whose expression is generally decreased significantly in patients with hepatoma. The proliferation of cancer cells with low expression of MnSOD exhibit high sensitivity to the elevated expression of MnSOD. However, due to the lack of ability to penetrate the cell membrane, the direct use and study of SOD for cancer treatment are largely hampered. In this work, cell penetrating peptide TAT was fused to the N-terminus of MnSOD to facilitate the penetration of MnSOD through cell membranes. Results showed that TAT-MnSOD wt treatment induced evident inhibitory effect on the proliferation of heptoma, with minimal effect on normal cells. It was further demonstrated that both the penetration of cells and enzymatic activity of MnSOD are essential to its inhibitory function, because only TAT-MnSOD wt, not inactive TAT-MnSOD mutant or MnSOD could successfully inhibit cell proliferation and reduce the intra-celluar reactive oxygen species (ROS). In addition, the lower oxidative stress delayed the cell cycle at G2/M and significantly slowed HepG2 cell growth in association with the dephosphorylation of survivin. Our results help in understanding the regulatory effects of MnSOD on cell viability and redox homestasis of heptoma and promise potential applications of TAT-MnSOD wt for clinical cancer therapy.

Gill BS, Kumar S, Navgeet
Evaluating anti-oxidant potential of ganoderic acid A in STAT 3 pathway in prostate cancer.
Mol Biol Rep. 2016; 43(12):1411-1422 [PubMed] Related Publications
Evaluating anti-oxidant potential of Ganoderic acid A in STAT 3 pathway in Prostate cancer. Molecular docking and ADMET activities of different isoforms of ganoderic acid on STAT 3 pathway were performed by Maestro 9.6 (Schrödinger Inc). The ganoderic acid A is best-docked among isoforms which analyses the expression level of antioxidant and STAT 3 pathway in PC-3 cells. The receptor-based molecular docking reveals the best binding interaction of SH2 domain of STAT3 and ganoderic acid A with GScore (-6.134), kcal/mol, Lipophilic EvdW (-1.83), Electro (-1.1), Glide emodel (-31.857), H bond (1.98), MM-GBSA (-69.555). The molecular docking QikProp analyzed the absorption, distribution, metabolism, excretion, and toxicity (ADME/T). The ganoderic acid A is best-docked among isoforms which downregulates the expression of STAT 3 in PC-3 cells. Moreover, ganoderic acid A inhibits proliferation, viability, ROS, DPPH, and analyzed the expression of SOD1, SOD2, and SOD3 by Real time PCR in a PC-3 cell in a dose-dependent manner. Molecular docking revealed the mechanistic binding of Ganoderic acid A in STAT3 signaling, which inhibits the proliferation, viability, and ROS in PC-3 cells.

Yi S, Niu D, Bai F, et al.
Soluble Expression of a Human MnSOD and Hirudin Fusion Protein in Escherichia coli, and Its Effects on Metastasis and Invasion of 95-D Cells.
J Microbiol Biotechnol. 2016; 26(11):1881-1890 [PubMed] Related Publications
Manganese superoxide dismutase (MnSOD) is a vital enzyme that protects cells from free radicals through eliminating superoxide radicals (O²⁻). Hirudin, a kind of small active peptide molecule, is one of the strongest anticoagulants that can effectively cure thrombus diseases. In this study, we fused Hirudin to the C terminus of human MnSOD with the GGGGS linker to generate a novel dual-feature fusion protein, denoted as hMnSOD-Hirudin. The hMnSOD-Hirudin gene fragment was cloned into the pET15b (SmaI, CIAP) vector, forming a recombinant pET15b-hMnSOD-Hirudin plasmid, and then was transferred into Escherichia coli strain Rosetta-gami for expression. SDS-PAGE was used to detect the fusion protein, which was expected to be about 30 kDa upon IPTG induction. Furthermore, the hMnSOD-Hirudin protein was heavily detected as a soluble form in the supernatant. The purification rate observed after Ni NTA affinity chromatography was above 95%. The hMnSOD-Hirudin protein yield reached 67.25 mg per liter of bacterial culture. The identity of the purified protein was confirmed by western blotting. The hMnSOD-Hirudin protein activity assay evinced that the antioxidation activity of the hMnSOD-Hirudin protein obtained was 2,444.0 ± 96.0 U/mg, and the anticoagulant activity of the hMnSOD-Hirudin protein was 599.0 ± 35.0 ATU/mg. In addition, in vitro bioactivity assay showed that the hMnSODHirudin protein had no or little cytotoxicity in H9c2, HK-2, and H9 (human CD₄⁺, T cell) cell lines. Transwell migration assay and invasion assay showed that the hMnSOD-Hirudin protein could suppress human lung cancer 95-D cell metastasis and invasion in vitro.

Laukkanen MO
Extracellular Superoxide Dismutase: Growth Promoter or Tumor Suppressor?
Oxid Med Cell Longev. 2016; 2016:3612589 [PubMed] Free Access to Full Article Related Publications
Extracellular superoxide dismutase (SOD3) gene transfer to tissue damage results in increased healing, increased cell proliferation, decreased apoptosis, and decreased inflammatory cell infiltration. At molecular level, in vivo SOD3 overexpression reduces superoxide anion (O2 (-)) concentration and increases mitogen kinase activation suggesting that SOD3 could have life-supporting characteristics. The hypothesis is further strengthened by the observations showing significantly increased mortality in conditional knockout mice. However, in cancer SOD3 has been shown to either increase or decrease cell proliferation and survival depending on the model system used, indicating that SOD3-derived growth mechanisms are not completely understood. In this paper, the author reviews the main discoveries in SOD3-dependent growth regulation and signal transduction.

Lim S, Liu H, Madeira da Silva L, et al.
Immunoregulatory Protein B7-H3 Reprograms Glucose Metabolism in Cancer Cells by ROS-Mediated Stabilization of HIF1α.
Cancer Res. 2016; 76(8):2231-42 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
B7-H3 is a member of B7 family of immunoregulatory transmembrane glycoproteins expressed by T cells. While B7-H3 overexpression is associated with poor outcomes in multiple cancers, it also has immune-independent roles outside T cells and its precise mechanistic contributions to cancer are unclear. In this study, we investigated the role of B7-H3 in metabolic reprogramming of cancer cells in vitro and in vivo We found that B7-H3 promoted the Warburg effect, evidenced by increased glucose uptake and lactate production in B7-H3-expressing cells. B7-H3 also increased the protein levels of HIF1α and its downstream targets, LDHA and PDK1, key enzymes in the glycolytic pathway. Furthermore, B7-H3 promoted reactive oxygen species-dependent stabilization of HIF1α by suppressing the activity of the stress-activated transcription factor Nrf2 and its target genes, including the antioxidants SOD1, SOD2, and PRX3. Metabolic imaging of human breast cancer xenografts in mice confirmed that B7-H3 enhanced tumor glucose uptake and tumor growth. Together, our results illuminate the critical immune-independent contributions of B7-H3 to cancer metabolism, presenting a radically new perspective on B7 family immunoregulatory proteins in malignant progression. Cancer Res; 76(8); 2231-42. ©2016 AACR.

Coskun C, Verim A, Farooqi AA, et al.
Are there possible associations between MnSOD and GPx1 gene variants for laryngeal cancer risk or disease progression?
Cell Mol Biol (Noisy-le-grand). 2016; 62(5):25-30 [PubMed] Related Publications
Laryngeal squamous cell carcinoma (LSCC) is a multifaceted and genomically complex disease and cellular and preclinical studies have demystified wide ranging molecular mechanisms which underpin its development and progression and resistance against wide ranging molecular therapeutics. Oxidative stress is a widely studied molecular mechanism and reportedly involved in carcinogenesis. Increasingly it is being realized that accumulation of Reactive Oxygen Species (ROS) activates defensive mechanism to counteract oxidative stress induced damage. Manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx) are important members of defensive machinery. We investigated whether the polymorphisms of MnSOD (Ala-9Val, rs4880) and GPx1 (Pro198Leu, rs1050450) are associated with LSCC and also evaluated possible interactions between these polymorphisms and various lifestyle factors or pathological features of patients. For this purpose, 67 LSCC patients and 73 healty controls were enrolled. Molecular assessment of MnSOD and GPx1 variants were determined with polymerase chain reaction-restriction fragment length polymorphism techniques. We found that the frequency of both heterozygous PL genotype and P allele was considerably higher in patients with advanced tumor stage (T3/T4) than in those with early tumor stage (T1/T2) (OR= 5.106; 95% CI=1.372-19.004; p<0.001, OR=5.787; 95% CI =1.564-21.414; p<0.001 respectively). Although the frequency of ValVal/LL combine genotype was significantly decreased (OR=0.204, 95% CI=0.055-0.760; p=0.021), the frequency of ValAla/PL combine genotypes was higher in patients with stage T3/T4 than in those patients with stage T1/T2 (p=0.027). Consequently, we have concluded that variants of GPx1 and MnSOD should not be considered as a risk factor of LSCC, only may be accepted as a prognostic markers. Use of new technologies such as metabolomics and deep DNA sequencing will prove to be helpful in developing a deeper knowledge related to how cancer cell metabolism adapts and provides a buffer against increased oxidative stress.

Cui Y, She K, Tian D, et al.
miR-146a Inhibits Proliferation and Enhances Chemosensitivity in Epithelial Ovarian Cancer via Reduction of SOD2.
Oncol Res. 2016; 23(6):275-82 [PubMed] Related Publications
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, accounting for 90% of all ovarian cancer. Dysregulation of miRNAs is associated with several types of EOC. In the current research, we aimed to study the role of abnormal expression of miR-146a in the development of EOC and to elucidate the possible molecular mechanisms. Compared with control samples, mRNA expression of miR-146a was significantly decreased in EOC tissues and cell lines. Overexpression of miR-146a prohibited cell proliferation, enhanced apoptosis, and increased sensitivity to chemotherapy drugs in EOC cells. In contrast, downregulation of miR-146a promoted cell proliferation, suppressed apoptosis, and decreased sensitivity to chemotherapy drugs in EOC cells. Overexpression of miR-146a increased the reactive oxygen species (ROS) level and decreased SOD2 mRNA and protein expression. Downregulation of miR-146a increased SOD2 mRNA and protein expression. Overexpression of SOD2 significantly inhibited miR-146a mimics-induced suppression of cell proliferation and the increase of apoptosis and chemosensitivity. In conclusion, we identify miR-146a as a potential tumor suppressor in patients with EOC. miR-146a downregulates the expression of SOD2 and enhances ROS generation, leading to increased apoptosis, inhibition of proliferation, and enhanced sensitivity to chemotherapy. The data demonstrate that the miR-146a/SOD2/ROS pathway may serve as a novel therapeutic target and prognostic marker in patients with EOC.

Peng CY, You BJ, Lee CL, et al.
The Roles of 4β-Hydroxywithanolide E from Physalis peruviana on the Nrf2-Anti-Oxidant System and the Cell Cycle in Breast Cancer Cells.
Am J Chin Med. 2016; 44(3):617-36 [PubMed] Related Publications
4[Formula: see text]-Hydroxywithanolide E is an active component of the extract of Physalis peruviana that has been reported to exhibit antitumor effects. Although the involvement of reactive oxygen species (ROS) production and the ataxia-telangiectasia mutated protein (ATM)-dependent DNA damage signaling pathway in 4[Formula: see text]-hydroxywithanolide E-induced apoptosis of breast cancer MCF-7 cells was demonstrated in our previous study, the relationship between ROS production and the cellular defense system response in 4[Formula: see text]-hydroxywithanolide E-induced cell death requires further verification. The present study suggests that ROS play an important role in 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in which anti-oxidants, such as glutathione or N-acetylcysteine, can resist the 4[Formula: see text]-hydroxywithanolide E-induced accumulation of ROS and cell death. Furthermore, N-acetylcysteine or glutathione can reverse the 4[Formula: see text]-hydroxywithanolide E-induced changes in the cell cycle distribution and the expression of cell cycle regulators. We found that the 4[Formula: see text]-hydroxywithanolide E-induced ROS accumulation was correlated with the upregulation of Nrf2 and Nrf2-downstream genes, such as antioxidative defense enzymes. In general, the activity of Nrf2 is regulated by the Ras signalling pathway. However, we demonstrated that Nrf2 was activated during 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in spite of the 4[Formula: see text]-hydroxywithanolide E-induced inhibition of the Ras/Raf/ERK pathway. The activity and protein expression of superoxide dismutase and catalase were involved in the 4[Formula: see text]-hydroxywithanolide E-induced ROS production in MCF-7 cells. Furthermore, 4[Formula: see text]-hydroxywithanolide E was demonstrated to significantly reduce the sizes of the tumor nodules in the human breast cancer MDA-MB231 xenograft tumor model.

Zhang R, Zhang X, Ma B, et al.
Enhanced antitumor effect of combining TRAIL and MnSOD mediated by CEA-controlled oncolytic adenovirus in lung cancer.
Cancer Gene Ther. 2016; 23(6):168-77 [PubMed] Related Publications
Lung cancer, especially adenocarcinoma, is one of the leading causes of death in the world. Carcinoembryonic antigen (CEA), a superb non-small-cell lung cancer marker candidate, showed a beneficial effect in cancer therapy with oncolytic adenovirus in recent studies. Cancer-targeting dual gene-virotherapy delivers two therapeutic genes, linked by a connexon, in the replication-deficient vector instead of one gene so that they can work in common. In this study, we constructed a tumor-specific oncolytic adenovirus, CD55-TRAIL-IETD-MnSOD. The virus has the fusion protein complementary DNAs for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and for manganese superoxide dismutase (MnSOD) complementary DNA linked through a 4-amino acid caspase-8 cleavage site (IETD), and uses a CEA promoter to control virus E1A express. This is the first work to use a CEA promoter-regulated oncolytic adenovirus carrying two therapeutic genes for cancer research. Its targeting and anticancer capacity was evaluated by in vitro and in vivo experiments. The results indicated that CD55-TRAIL-IETD-MnSOD caused more cell apoptosis than CD55-TRAIL or CD55-MnSOD alone, or their combination in vitro, with low cytotoxicity of normal cells. In the A549 tumor xenograft model in nude mice, data showed that CD55-TRAIL-IETD-MnSOD could effectively suppress tumor growth than single gene groups, with no histological damage in liver, spleen or kidney tissues. Thus, the CEA-regulated dual-gene oncolytic virus CD55-TRAIL-IETD-MnSOD may be a novel potential therapy for lung cancer.

Chaisiriwong L, Wanitphakdeedecha R, Sitthinamsuwan P, et al.
A Case-Control Study of Involvement of Oxidative DNA Damage and Alteration of Antioxidant Defense System in Patients with Basal Cell Carcinoma: Modulation by Tumor Removal.
Oxid Med Cell Longev. 2016; 2016:5934024 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Oxidative damage has been suggested to play a role in the pathogenesis of basal cell carcinoma (BCC). This study illustrated an involvement of oxidative DNA damage and changes in antioxidant defenses in BCC by conducting a case-control study (24 controls and 24 BCC patients) and assessing urinary 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dGuo), plasma antioxidant defenses including catalase (CAT), glutathione peroxidase (GPx), NQO1, and total superoxide dismutase (SOD) activities, and glutathione (GSH) levels before surgery and 1 month after surgery. 8-oxo-dGuo expressions as well as protein and mRNA expressions of DNA repair enzyme hOGG1 and antioxidant defenses (CAT, GCLC, GPx, Nrf2, and MnSOD) in nonneoplastic epidermis of control and BCC tissues were also determined. This study observed induction in urinary 8-oxo-dGuo, increased 8-oxo-dGuo expression, and reduced hOGG1 protein and mRNA in BCC tissues, decreased activities of CAT, GPx, and NQO1, but elevated SOD activities and GSH levels in BCC patients and reduction of all antioxidant proteins and genes studied in BCC tissues. Furthermore, decreased plasma antioxidant activities in BCC patients were restored at 1 month after operation compared with preoperative levels. Herein, we concluded that BCC patients were associated with oxidative DNA damage and depletion of antioxidant defenses and surgical removal of BCC correlated with improved redox status.

He P, Sun L, Zhu D, et al.
Knock-Down of Endogenous Bornavirus-Like Nucleoprotein 1 Inhibits Cell Growth and Induces Apoptosis in Human Oligodendroglia Cells.
Int J Mol Sci. 2016; 17(4):435 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Endogenous bornavirus-like nucleoprotein elements (EBLNs) have been discovered in the genomes of various animals including humans, whose functions have been seldom studied. To explore the biological functions of human EBLNs, we constructed a lentiviral vector expressing a short-hairpin RNA against human EBLN1, which successfully inhibited EBLN1 expression by above 80% in infected human oligodendroglia cells (OL cells). We found that EBLN1 silencing suppressed cell proliferation, induced G2/M phase arrest, and promoted apoptosis in OL cells. Gene expression profiling demonstrated that 1067 genes were up-regulated, and 2004 were down-regulated after EBLN1 silencing. The top 10 most upregulated genes were PI3, RND3, BLZF1, SOD2, EPGN, SBSN, INSIG1, OSMR, CREB3L2, and MSMO1, and the top 10 most-downregulated genes were KRTAP2-4, FLRT2, DIDO1, FAT4, ESCO2, ZNF804A, SUV420H1, ZC3H4, YAE1D1, and NCOA5. Pathway analysis revealed that these differentially expressed genes were mainly involved in pathways related to the cell cycle, the mitogen-activated protein kinase pathway, p53 signaling, and apoptosis. The gene expression profiles were validated by using quantitative reverse transcription polymerase chain reaction (RT-PCR) for detecting these 20 most-changed genes. Three genes closely related to glioma, RND3, OSMR, and CREB3L2, were significantly upregulated and might be the key factors in EBLN1 regulating the proliferation and apoptosis of OL cells. This study provides evidence that EBLN1 plays a key role in regulating cell life and death, thereby opening several avenues of investigation regarding EBLN1 in the future.

Zhong BL, Bian LJ, Wang GM, et al.
Identification of key genes involved in HER2-positive breast cancer.
Eur Rev Med Pharmacol Sci. 2016; 20(4):664-72 [PubMed] Related Publications
OBJECTIVE: As an invasive cancer, breast cancer is the most common tumour in women and is with high mortality. To study the mechanisms of HER2-positive breast cancer, we analyzed microarray of GSE52194.
MATERIALS AND METHODS: GSE52194 was downloaded from Gene Expression Omnibus including 5 HER2-positive breast cancer samples and 3 normal breast samples. Using cuffdiff software, differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DE-lncRNAs) were screened. Functions of the DEGs were analyzed by Gene Ontology (GO) and pathway enrichment analyses. Then, protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape and modules of the PPI network were screened by CFinder. Moreover, lncRNA-DEG pairs were screened.
RESULTS: Total 209 lncRNA transcriptions were predicted, and 996 differentially expressed transcriptions were screened. Besides, FOS had interaction relationships with EGR1 and SOD2 separately in module E and F of the PPI network for the DEGs. Moreover, there were many lncRNA-DEG pairs (e.g. TCONS_00003876-EGR1, TCONS_00003876-FOS, lnc-HOXC4-3:1-FOS, lnc-HOXC4-3:1-BCL6B, lnc-TEAD4-1:1-FOS and lnc-TEAD4-1:1-BCL6B), meanwhile, co-expressed DEGs of TCONS_00003876, lnc-HOXC4-3:1 and lnc-TEAD4-1:1 were enriched in p53 signaling pathway, MAPK signaling pathway and cancer-related pathways, respectively.
CONCLUSIONS: ANXA1, EGR1, BCL6, SOD2, FOS, TCONS_00003876, lnc-HOXC4-3:1 and lnc-TEAD4-1:1 might play a role in HER2-positive breast cancer.

Chung MJ, Lee S, Park YI, et al.
Neuroprotective effects of phytosterols and flavonoids from Cirsium setidens and Aster scaber in human brain neuroblastoma SK-N-SH cells.
Life Sci. 2016; 148:173-82 [PubMed] Related Publications
AIMS: We investigated the neuroprotective effects and action mechanism of three major compounds [daucosterol (Dau), pectolinarin (Pec), and astragalin (Ast)] isolated from edible plants against H2O2-induced cell death of human brain neuroblastoma SK-N-SH cells.
MAIN METHODS: Cytotoxicity was determined by MTT and lactate dehydrogenase (LDH) assays. Apoptotic cell death was monitored by annexin V-FITC/PI double staining and by TUNEL assay. The formation of reactive oxygen species (ROS), expression of antioxidant enzymes and phosphorylation of mitogen-activated protein kinase (MAPK) were determined by 2,7-dichlorofluorescein diacetate (DCF-DA) assay, RT-PCR, and western blotting, respectively.
KEY FINDINGS: The ethyl acetate fractions from Cirsium setidens (CSEA) and Aster scaber (ASEA) showed neuroprotective effects in SK-N-SH cells. The phytochemicals were isolated from CSEA and ASEA and identified by spectral analyses, as β-sitosterol, Dau, Pec, Ast, or isoquercitrin. Pretreatment with Dau, Pec, or Ast showed protective effects against H2O2-induced cell death and inhibited ROS generation by oxidative stress. HO-1 mRNA and protein levels were increased by the presence of H2O2 and were further elevated by pretreatment with Dau and Ast. Dau pretreatment resulted in further increases of H2O2-induced enhancement in levels of CAT and SOD2. Pretreatment with Dau, Pec, and Ast inhibited phosphorylation of MAPK, such as extracellular protein regulated protein kinase, p38, and c-Jun N-terminal kinase by H2O2.
SIGNIFICANCE: Dau exerts its neuroprotective effects by down regulation of MAPK pathways and upregulation of the HO-1, CAT and SOD2 antioxidant genes and is associated with reduced oxidative stress in SK-N-SH cells.

Koo JS, Kim JW, Yoon JS
Expression of Autophagy and Reactive Oxygen Species-Related Proteins in Lacrimal Gland Adenoid Cystic Carcinoma.
Yonsei Med J. 2016; 57(2):482-9 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
PURPOSE: To investigate the difference of expression of autophagy and reactive oxygen species (ROS) related proteins in adenoid cystic carcinoma (ACC) of lacrimal gland in comparison with ACC of salivary gland.
MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tissue samples from patients pathologically diagnosed as lacrimal gland ACC (n=11) and salivary gland ACC (n=64) were used. Immunochemistry was used to measure expression of autophagy related proteins [beclin-1, light chain (LC) 3A, LC3B, p62, and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)] and ROS related proteins [catalase, thioredoxinreductase, glutathione S-transferasepi (GSTpi), thioredoxin interacting protein, and manganese superoxide dismutase (MnSOD)]. The prognostic factors related to disease-free and overall survival (OS) in lacrimal gland ACC by log-rank tests, were determined.
RESULTS: GSTpi in stromal cells was more highly expressed in lacrimal gland ACC (p=0.006), however, MnSOD in epithelial cells was expressed more in salivary gland ACC (p=0.046). LC3B positivity and BNIP3 positivity in epithelial component were associated with shorter disease-free survival (both p=0.002), and LC3A positivity in stromal component was the factor related to shorter OS (p=0.005).
CONCLUSION: This is the first study to demonstrate the expression of autophagy and ROS related proteins in lacrimal gland ACC in comparison with the salivary gland ACC, which would provide a basis for further study of autophagy and ROS mechanism as novel therapeutic targets in lacrimal gland ACC.

Bănescu C, Iancu M, Trifa AP, et al.
From Six Gene Polymorphisms of the Antioxidant System, Only GPX Pro198Leu and GSTP1 Ile105Val Modulate the Risk of Acute Myeloid Leukemia.
Oxid Med Cell Longev. 2016; 2016:2536705 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Oxidative stress might contribute to the occurrence of cancers, including the hematological ones. Various genetic polymorphisms were shown to increase the quantity of reactive oxygen species, a phenomenon that is able to induce mutations and thus promote cancers. The purpose of the study was to evaluate the association between CAT C262T, GPX1 Pro198Leu, MnSOD Ala16Val, GSTM1, GSTT1, and GSTP1 Ile105Val gene polymorphisms and acute myeloid leukemia risk, in a case-control study comprising 102 patients and 303 controls. No association was observed between AML and variant genotypes of CAT, MnSOD, GSTM1, and GSTT1 polymorphisms. Our data revealed a statistically significant difference regarding the frequencies of GPX1 Pro198Leu and GSTP1 Ile105Val variant genotypes between AML patients and controls (p < 0.001). Our results showed no association in the distribution of any of the CAT C262T, GPX1 Pro198Leu, GSTM1, GSTT1, and GSTP1 polymorphisms regarding age, gender, FAB subtype, cytogenetic risk groups, FLT3 and DNMT3 gene mutations, and overall survival. Our data suggests that the presence of variant allele and genotype of GPX1 Pro198Leu and GSTP1 Ile105Val gene polymorphisms may modulate the risk of developing AML.

Velmurugan BK, Yang HH, Sung PJ, Weng CF
Excavatolide B inhibits nonsmall cell lung cancer proliferation by altering peroxisome proliferator activated receptor gamma expression and PTEN/AKT/NF-Kβ expression.
Environ Toxicol. 2017; 32(1):290-301 [PubMed] Related Publications
Marine organisms are proven to be rich source of secondary metabolites that can be used to treat various diseases. Excavatolide B (Exc.B), the most abundant metabolite was found in the marine coral Briareum excavatum exhibits cytotoxic effects against lung cancer cell. Treatment of the A549 cells with Exc.B significantly reduced its cell viability and induced cell cycle arrest at subG1 phase in a dose- and time-dependent manner, respectively. Apoptosis induction by Exc.B was further confirmed by decreased pro-caspase 3 expressions and increased proteolytic cleavage of poly (ADP-ribose) polymerase (PARP) expression. Furthermore, Exc.B increased reactive oxygen species (ROS) and reactive nitrogen species (RNS) and also decreased the antioxidant enzymes such as, Catalase, GPx, SOD, GST, and GSH. The proteomic analysis data revealed that total thirty six proteins were altered by Exc.B. STRING database showed that most of the altered proteins have no interaction between each other. Based on these data, KSR1, RuVBL2, PPAR-γ, and Tenascin X proteins were chosen to validate the 2DE data by Western blotting. Additional experiments demonstrated that Exc.B induced PTEN expression and inhibited pAKT and NF-kB expression. These results provide a novel insight into mechanisms underlying the inhibition of A549 cells growth by excavatolide B. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 290-301, 2017.

Naushad SM, Ramaiah MJ, Pavithrakumari M, et al.
Artificial neural network-based exploration of gene-nutrient interactions in folate and xenobiotic metabolic pathways that modulate susceptibility to breast cancer.
Gene. 2016; 580(2):159-68 [PubMed] Related Publications
In the current study, an artificial neural network (ANN)-based breast cancer prediction model was developed from the data of folate and xenobiotic pathway genetic polymorphisms along with the nutritional and demographic variables to investigate how micronutrients modulate susceptibility to breast cancer. The developed ANN model explained 94.2% variability in breast cancer prediction. Fixed effect models of folate (400 μg/day) and B12 (6 μg/day) showed 33.3% and 11.3% risk reduction, respectively. Multifactor dimensionality reduction analysis showed the following interactions in responders to folate: RFC1 G80A × MTHFR C677T (primary), COMT H108L × CYP1A1 m2 (secondary), MTR A2756G (tertiary). The interactions among responders to B12 were RFC1G80A × cSHMT C1420T and CYP1A1 m2 × CYP1A1 m4. ANN simulations revealed that increased folate might restore ER and PR expression and reduce the promoter CpG island methylation of extra cellular superoxide dismutase and BRCA1. Dietary intake of folate appears to confer protection against breast cancer through its modulating effects on ER and PR expression and methylation of EC-SOD and BRCA1.

Cacabelos D, Ramírez-Núñez O, Granado-Serrano AB, et al.
Early and gender-specific differences in spinal cord mitochondrial function and oxidative stress markers in a mouse model of ALS.
Acta Neuropathol Commun. 2016; 4:3 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a gender bias towards major prevalence in male individuals. Several data suggest the involvement of oxidative stress and mitochondrial dysfunction in its pathogenesis, though differences between genders have not been evaluated. For this reason, we analysed features of mitochondrial oxidative metabolism, as well as mitochondrial chain complex enzyme activities and protein expression, lipid profile, and protein oxidative stress markers, in the Cu,Zn superoxide dismutase with the G93A mutation (hSOD1-G93A)- transgenic mice and Neuro2A(N2A) cells overexpressing hSOD1-G93A.
RESULTS AND CONCLUSIONS: Our results show that overexpression of hSOD1-G93A in transgenic mice decreased efficiency of mitochondrial oxidative phosphorylation, located at complex I, revealing a temporal delay in females with respect to males associated with a parallel increase in selected markers of protein oxidative damage. Further, females exhibit a fatty acid profile with higher levels of docosahexaenoic acid at 30 days. Mechanistic studies showed that hSOD1-G93A overexpression in N2A cells reduced complex I function, a defect prevented by 17β-estradiol pretreatment. In conclusion, ALS-associated SOD1 mutation leads to delayed mitochondrial dysfunction in female mice in comparison with males, in part attributable to the higher oestrogen levels of the former. This study is important in the effort to further understanding of whether different degrees of spinal cord mitochondrial dysfunction could be disease modifiers in ALS.

Codini M, Cataldi S, Lazzarini A, et al.
Why high cholesterol levels help hematological malignancies: role of nuclear lipid microdomains.
Lipids Health Dis. 2016; 15:4 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
BACKGROUND: Diet and obesity are recognized in the scientific literature as important risk factors for cancer development and progression. Hypercholesterolemia facilitates lymphoma lymphoblastic cell growth and in time turns in hypocholesterolemia that is a sign of tumour progression. The present study examined how and where the cholesterol acts in cancer cells when you reproduce in vitro an in vivo hypercholesterolemia condition.
METHODS: We used non-Hodgkin's T cell human lymphoblastic lymphoma (SUP-T1 cell line) and we studied cell morphology, aggressiveness, gene expression for antioxidant proteins, polynucleotide kinase/phosphatase and actin, cholesterol and sphingomyelin content and finally sphingomyelinase activity in whole cells, nuclei and nuclear lipid microdomains.
RESULTS: We found that cholesterol changes cancer cell morphology with the appearance of protrusions together to the down expression of β-actin gene and reduction of β-actin protein. The lipid influences SUP-T1 cell aggressiveness since stimulates DNA and RNA synthesis for cell proliferation and increases raf1 and E-cadherin, molecules involved in invasion and migration of cancer cells. Cholesterol does not change GRX2 expression but it overexpresses SOD1, SOD2, CCS, PRDX1, GSR, GSS, CAT and PNKP. We suggest that cholesterol reaches the nucleus and increases the nuclear lipid microdomains known to act as platform for chromatin anchoring and gene expression.
CONCLUSION: The results imply that, in hypercholesterolemia conditions, cholesterol reaches the nuclear lipid microdomains where activates gene expression coding for antioxidant proteins. We propose the cholesterolemia as useful parameter to monitor in patients with cancer.

Bhakkiyalakshmi E, Suganya N, Sireesh D, et al.
Carvacrol induces mitochondria-mediated apoptosis in HL-60 promyelocytic and Jurkat T lymphoma cells.
Eur J Pharmacol. 2016; 772:92-8 [PubMed] Related Publications
The aim of the present study was to investigate the effect of carvacrol, a phenolic monoterpenoid on the induction of apoptosis in HL-60 (Human acute promyelocytic leukemia cells) and Jurkat (human T lymphocyte cells) cells. Carvacrol showed a potent cytotoxic effect on both cells with dose-dependent increase in the level of free radical formation as measured by an oxidation sensitive fluorescent dye, 2,7-dichlorodihydrofluorescein diacetate (H2DCFDA) levels. The reduction in the level of antioxidants such as catalase (CAT) and superoxide dismutase (SOD) (P<0.05) was observed in carvacrol-treated cells. The major cytotoxic effect appears to be intervened by the induction of apoptotic cell death as assessed by annexin-V labeling assay using flow cytometry. Western blot analysis showed that Bax expression was increased, whereas Bcl-2 expression was significantly decreased in carvacrol exposed HL-60 cells and Jurkat cells. Further studies revealed that the dissipation of mitochondrial membrane potential of intact cells was accompanied by the activation of caspase-3. Our results found that the potential mechanism of cellular apoptosis induced by carvacrol is mediated by caspase-3 and is associated with the collapse of mitochondrial membrane potential, generation of free radicals, and depletion of the intracellular antioxidant pool.

Lai Y, Yu X, Lin X, He S
Inhibition of mTOR sensitizes breast cancer stem cells to radiation-induced repression of self-renewal through the regulation of MnSOD and Akt.
Int J Mol Med. 2016; 37(2):369-77 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
The sensitization of breast cancer stem cells (BrCSCs) to the inhibitive effects of radiotherapy through adjuvant therapy which targets oncogenic pathways represents a prospective strategy for improving the effect of radiation in patients with triple-negative breast cancer (TNBC). Mammalian target of rapamycin (mTOR) activation is one of the most frequent events in human malignancies, and is critical for sustaining the self‑renewing ability of cancer stem cells (CSCs); inhibition by rapamycin is an effective and promising strategy in anticancer treatments. In the present study, we found that mTOR activity was closely related to the self-renewal ability of BrCSCs, and in triple negative MDA-MB-453 and MDA-MB‑468 cells, rapamycin repression of mTOR phosphorylation decreased the number of mammospheres and helped to sensitize the resistant CSCs to low-dose radiation therapy. By inhibiting mTOR and mitochondrial manganese superoxide dismutase (MnSOD), we confirmed that rapamycin functioned through the mTOR/MnSOD/reactive oxygen species (ROS) signaling pathway, and the existence of Akt governed the rapamycin‑induced asymmetric division (AD) of stem cells in cases of radiation‑treated breast cancer. The synergic effects of rapamycin and low-dose radiation induced the AD of stem cells, which then resulted in a decrease in the number of mammospheres, and both were mediated by MnSOD. Governed by Akt, the consequent inhibition of ROS formation and oxidative stress preserved the AD mode of stem cells, which is critical for an improved radiotherapy response in clinical treatment, as the tumor group is thus easier to eliminate with radiation therapy. We posit that an in-depth understanding of the interaction of radiation with CSCs has enormous potential and will make radiation even better and more effective.

Yanar K, Çakatay U, Aydın S, et al.
Relation between Endothelial Nitric Oxide Synthase Genotypes and Oxidative Stress Markers in Larynx Cancer.
Oxid Med Cell Longev. 2016; 2016:4985063 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Nitric oxide synthase (eNOS/NOS3) is responsible for the endothelial synthesis of nitric oxide (NO(•)). G894T polymorphism leads to the amino acid substitution from Glu298Asp that causes lower NOS3 activity and basal NO(•) production in NOS3 894T (298Asp) allele carriers compared with the GG homozygotes. NO(•) acts as an antioxidant protecting against Fenton's reaction which generates highly reactive hydroxyl radicals. Allelic variation of NOS3 may influence an individual's risk of laryngeal cancer (LC). In the current study we have examined the possible relationship between NOS3 G894T genotypes and various systemic oxidative damage markers such as protein carbonyl, advanced oxidation protein products, Cu, Zn-superoxide dismutase, thiol group fractions, and lipid hydroperoxides in LC patients. Genotyping was carried out by PCR-RFLP. In LC patients with TT genotype, Cu, Zn-superoxide dismutase activities and nonprotein thiol levels were significantly higher than the controls. In patients with GT and GG genotype, high levels of lipid hydroperoxides showed statistical significance when compared to controls. Our results indicate a potential relationship among G894T polymorphism of NOS3, and impaired redox homeostasis. Further studies are required to determine the role of NOS3 gene polymorphism and impaired plasma redox homeostasis.

Silvis AM, McCormick ML, Spitz DR, Kiningham KK
Redox balance influences differentiation status of neuroblastoma in the presence of all-trans retinoic acid.
Redox Biol. 2016; 7:88-96 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Neuroblastoma is the most common extra-cranial solid tumor in childhood; and patients in stage IV of the disease have a high propensity for tumor recurrence. Retinoid therapy has been utilized as a means to induce differentiation of tumor cells and to inhibit relapse. In this study, the expression of a common neuronal differentiation marker [neurofilament M (NF-M)] in human SK-N-SH neuroblastoma cells treated with 10μM all-trans retinoic acid (ATRA) showed significantly increased expression in accordance with reduced cell number. This was accompanied by an increase in MitoSOX and DCFH2 oxidation that could be indicative of increased steady-state levels of reactive oxygen species (ROS) such as O2(•-) and H2O2, which correlated with increased levels of MnSOD activity and immuno-reactive protein. Furthermore PEG-catalase inhibited the DCFH2 oxidation signal to a greater extent in the ATRA-treated cells (relative to controls) at 96h indicating that as the cells became more differentiated, steady-state levels of H2O2 increased in the absence of increases in peroxide-scavenging antioxidants (i.e., glutathione, glutathione peroxidase, and catalase). In addition, ATRA-induced stimulation of NF-M at 48 and 72h was enhanced by decreasing SOD activity using siRNA directed at MnSOD. Finally, treatment with ATRA for 96h in the presence of MnSOD siRNA or PEG-catalase inhibited ATRA induced increases in NF-M expression. These results provide strong support for the hypothesis that changes in steady-state levels of O2(•-) and H2O2 significantly contribute to the process of ATRA-induced differentiation in neuroblastoma, and suggest that retinoid therapy for neuroblastoma could potentially be enhanced by redox-based manipulations of superoxide metabolism to improve patient outcome.

Azzolin VF, Cadoná FC, Machado AK, et al.
Superoxide-hydrogen peroxide imbalance interferes with colorectal cancer cells viability, proliferation and oxaliplatin response.
Toxicol In Vitro. 2016; 32:8-15 [PubMed] Related Publications
The role of superoxide dismutase manganese dependent enzyme (SOD2) in colorectal cancer is presently insufficiently understood. Some studies suggest that high SOD2 levels found in cancer tissues are associated with cancer progression. However, thus far, the role of colorectal cancer superoxide-hydrogen peroxide imbalance has not yet been studied. Thus, in order to address this gap in extant literature, we performed an in vitro analysis using HT-29 colorectal cell line exposed to paraquat, which generates high superoxide levels, and porphyrin, a SOD2 mimic molecule. The effect of these drugs on colorectal cancer cell response to oxaliplatin was evaluated. At 0.1 μM concentration, both drugs exhibited cytotoxic and antiproliferative effect on colorectal cancer cells. However, this effect was more pronounced in cells exposed to paraquat. Paraquat also augmented the oxaliplatin cytotoxic and antiproliferative effects by increasing the number of apoptosis events, thus causing the cell cycle arrest in the S and M/G2 phases. The treatments were also able to differentially modulate genes related to apoptosis, cell proliferation and antioxidant enzyme system. However, the effects were highly variable and the results obtained were inconclusive. Nonetheless, our findings support the hypothesis that imbalance caused by increased hydrogen peroxide levels could be beneficial to cancer cell biology. Therefore, the use of therapeutic strategies to decrease hydrogen peroxide levels mainly during oxaliplatin chemotherapy could be clinically important to the outcomes of colorectal cancer treatment.

Latocha M, Zięba A, Polaniak R, et al.
MOLECULAR EFFECTS OF AMINE DERIVATIVES OF PHENOTHIAZINE ON CANCER CELLS C-32 AND SNB-19 IN VITRO.
Acta Pol Pharm. 2015 Sep-Oct; 72(5):909-15 [PubMed] Related Publications
Cancer therapy is challenging for scientists because of low effectiveness of so far existing therapies (especially in case of great invasiveness and advanced tumor stage). Such need for new drug development and search for more efficient new findings in therapeutical applications is therefore still valid. There are also conducted studies on modifying so far existing drugs and their new methods of usage in oncology practice. One of them is phenothiazine and its derivatives which are used in psychiatric treatment for years. They also exhibit antiprion, antiviral, antibacterial and antiprotozoal properties. Cytotoxic activity, influence on proliferation, ability to induce apoptosis suggest also a possibility of phenothiazine derivatives usage in cancer cells termination. The aim of our the study was to evaluate the influence of two amine derivatives of phenothiazine on cancer cells in vitro. Amelanotic melanoma C-32 cell line (ATCC) and glioma SNB-19 cells (DSMZ) were used in this study and two derivatives were analyzed. In view of examined substances tumor potential toxicity cells proliferation and viability exposed to phenothiazine derivatives were established. Cell cycle regulatory genes expression (TP53 and CDKN1A), S-phase marker--H3 gene and intracellular apoptosis pathway genes (BAX, BCL-2) were analyzed using RT-QPCR method. The influence of examined derivatives on total cell oxidative status (TOS), total antioxidative status (TAS), malondialdehyde concentration (MDA) and superoxide dismutase activity (SOD) were analyzed. As a result, examined phenothiazine derivatives cytotoxic action on C-32 and SNB-19 and also cells proliferation inhibition were determined. Cell cycle regulatory genes (TP53, CDKN1A) expression and protein products of genes involved in mitochondial apoptosis pathway (BAX, BCL-2) expression are changed by the presence of phenothiazine derivatives during culturing. There were also noted small changes in redox potential in cells exposed to two mentioned phenothiazine derivatives.

Yu W, Denu RA, Krautkramer KA, et al.
Loss of SIRT3 Provides Growth Advantage for B Cell Malignancies.
J Biol Chem. 2016; 291(7):3268-79 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
B cell malignancies comprise a diverse group of cancers that proliferate in lymph nodes, bone marrow, and peripheral blood. SIRT3 (sirtuin 3) is the major deacetylase within the mitochondrial matrix that promotes aerobic metabolism and controls reactive oxygen species (ROS) by deacetylating and activating isocitrate dehydrogenase 2 (IDH2) and superoxide dismutase 2 (SOD2). There is controversy as to whether SIRT3 acts as an oncogene or a tumor suppressor, and here we investigated its role in B cell malignancies. In mantle cell lymphoma patient samples, we found that lower SIRT3 protein expression was associated with worse overall survival. Further, SIRT3 protein expression was reduced in chronic lymphocytic leukemia primary samples and malignant B cell lines compared to primary B cells from healthy donors. This lower level of expression correlated with hyperacetylation of IDH2 and SOD2 mitochondrial proteins, lowered enzymatic activities, and higher ROS levels. Overexpression of SIRT3 decreased proliferation and diminished the Warburg-like phenotype in SIRT3-deficient cell lines, and this effect is largely dependent on deacetylation of IDH2 and SOD2. Lastly, depletion of SIRT3 from malignant B cell lines resulted in greater susceptibility to treatment with an ROS scavenger but did not result in greater sensitivity to inhibition of the hypoxia-inducible factor-1α pathway, suggesting that loss of SIRT3 increases proliferation via ROS-dependent but hypoxia-inducible factor-1α-independent mechanisms. Our study suggests that SIRT3 acts as a tumor suppressor in B cell malignancies, and activating the SIRT3 pathway might represent a novel therapeutic approach for treating B cell malignancies.

Salim EI, Abd El-Magid AD, Farara KM, Maria DS
Antitumoral and Antioxidant Potential of Egyptian Propolis Against the PC3 Prostate Cancer Cell Line.
Asian Pac J Cancer Prev. 2015; 16(17):7641-51 [PubMed] Related Publications
It has been shown previously that nutritional supplements rich in polyphenolic compounds play a significant role in prostate cancer chemoprevention. Propolis is a natural, resinous hive product that has several pharmacological activities including antimicrobial, antioxidant, anti-inflammatory, and antitumoral activities. The aim of this study was to compare the cytotoxic, antioxidant and antitumoral activities of an ethanolic extract of Egyptian propolis (EEP) in vitro with an established chemotherapeutic drug such as doxorubicin (DOX), and the effects of their combination against the PC3 human prostate cancer cell line. Cellular viability and IC50 levels with EEP, DOX and their (v/v) combination were detected by sulphorhodamine-B (SRB) assay after incubation of PC3 cells for 72 h with different doses (0, 0.01, 0.1, 1, 10 and 100 μg/ml). Two selected doses of IC50 and IC25 were applied to cells for 24h for antitumor evaluation assay of treatment compounds. EEP and its (v/v) combination with DOX showed significant antitumor potential besides high antioxidant properties of superoxide dismutase (SOD), total antioxidant capacity (TAC), catalase (CAT), nitric oxide (NO) and reduced glutathione (GSH) levels when compared with the control untreated cells. DNA fragmentation assay and semi quantitative RT-PCR analyses for p53 and Bax genes showed that EEP activated cellular apoptosis and increased the mRNA expression levels more than other treatment. In conclusion, EEP alone or in combination with DOX at both doses used here showed greater antioxidant, antiproliferative and apoptotic effects against the PC3 cell lines as compared to treatment with DOX alone. Therefore, EEP could be considered as a promising candidate for prostate cancer chemotherapy.

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