Genes regulated in human breast cancer cells overexpressing manganese-containing superoxide dismutase

Li, Zhongkui; Khaletskiy, Alexander; Wang, Jianyi; Wong, Jeffrey Y.C.; Oberley, Larry W.; Li, Jian Jian

doi:10.1016/s0891-5849(00)00468-8

Cited by 124 publications

(135 citation statements)

References 25 publications

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“…We have previously shown that overexpression of MnSOD in a murine fibrosarcoma cell line results in a decrease in the activity of Jun associated transcription factors resulting in a subsequent downregulation of target protooncogenes [8]. Additionally, our group and others have shown that MnSOD transgenic cell lines, relative to wild-type cells, have significantly slower growth rates, decreased colony formation and exhibit morphological changes consistent with a differentiated phenotype [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

All-trans-retinoic acid induces manganese superoxide dismutase in human neuroblastoma through NF-κB

Kiningham

Cardozo

Cook

et al. 2008

Free Radical Biology and Medicine

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Retinoids are signaling molecules that are involved in proliferation, differentiation and apoptosis during development. Retinoids exert their effects, in part, by binding to nuclear receptors, thereby altering gene expression. Clinical use of retinoids in the treatment of neuroblastoma is of interest due to their success in management of acute promyelocytic leukemia. Using the SK-N-SH human neuroblastoma cell line we investigated the effect of the differentiation agent, all-trans-retinoic acid (ATRA) on manganese superoxide dismutase (MnSOD) expression, an enzyme previously shown to enhance differentiation in vitro. Manganese superoxide dismutase mRNA, protein and activity levels increased in a time dependent manner upon treatment with ATRA. Nuclear levels of the NFκB proteins, p50 and p65, increased within 24 h of ATRA administration. This increase paralleled the degradation of the cytoplasmic inhibitor, IκB-β. Furthermore an increase in DNA binding activity to a NFκB element occurred within a 342 base pair enhancer (I2E) of the SOD2 gene with 10 μM ATRA treatment. Reporter analysis showed that ATRA-mediated I2E dependent luciferase expression was attenuated upon mutation of the NFκB element, suggesting a contribution of this transcription factor in retinoid-mediated upregulation of MnSOD. This study identifies SOD2 to be a retinoid responsive gene and demonstrates activation of the NFκB pathway in response to ATRA treatment of SK-N-SH cells. These results suggest signaling events involving NFκB and SOD2 may contribute to the effects of retinoids used in cancer therapy.

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Section: Introductionmentioning

confidence: 99%

All-trans-retinoic acid induces manganese superoxide dismutase in human neuroblastoma through NF-κB

Kiningham

Cardozo

Cook

et al. 2008

Free Radical Biology and Medicine

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

Section: Introductionmentioning

confidence: 99%

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

Hitchler¹,

Wikainapakul²,

Yu³

et al. 2006

Epigenetics

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

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“…As mitochondria respiration is the main source of O 2 KÀ generation in the cells, MnSOD is of prime importance in maintaining the cellular ROS balance. Genetic knockout studies in mice indicate that MnSOD, but not other SODs, is essential for cell survival (Carlsson et al, 1995;Li et al, 1995;Reaume et al, 1996). Although numerous studies have demonstrated altered antioxidant enzyme activity in a variety of solid tumours, ovarian cancer is unique because generation of ROS appears to be a risk factor for ovarian cancer (Murdoch, 2005).…”

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confidence: 99%

Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2

et al. 2008

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Chemoresistance and therapeutic selectivity are major obstacles to successful chemotherapy of ovarian cancer. Manganese superoxide disumutase (MnSOD) is an important antioxidant enzyme responsible for the elimination of superoxide radicals. We reported here that MnSOD was significantly elevated in ovarian cancer cells and its overexpression was one of the mechanisms that increased resistance to apoptosis in cancer cells. Knockdown of MnSOD by small-interfering RNA (siRNA) led to an increase in superoxide generation and sensitisation of ovarian cancer cells to the two front-line anti-cancer agents doxorubicin and paclitaxel whose action involved free-radical generation. This synergistic effect was not observed in non-transformed ovarian surface epithelial cells. Furthermore, our results revealed that this combination at the cellular level augmented activation of caspase-3 and caspase-9, but not caspase-8, suggesting involvement of an intrinsic apoptotic pathway. Evaluation of signalling pathways showed that MnSOD siRNA enhanced doxorubicin-and paclitaxel-induced phosphorylation of extracellular signal-regulated kinase 1/2. Akt activation was not affected. These results identify a novel chemoresistance mechanism in ovarian cancer, and show that combination of drugs capable of suppressing MnSOD with conventional chemotherapeutic agents may provide a novel strategy with a superior therapeutic index and advantage for the treatment of refractory ovarian cancer.

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Genes regulated in human breast cancer cells overexpressing manganese-containing superoxide dismutase

Cited by 124 publications

References 25 publications

All-trans-retinoic acid induces manganese superoxide dismutase in human neuroblastoma through NF-κB

All-trans-retinoic acid induces manganese superoxide dismutase in human neuroblastoma through NF-κB

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

Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2

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