Regulation of the high basal expression of the manganese superoxide dismutase gene in aggressive breast cancer cells

Ennen, Marie; Minig, Vanessa; Grandemange, Stéphanie; Touche, Nadège; Merlin, Jean‐Louis; Besancenot, Vanessa; Brunner, Emilie; Domenjoud, Lionel; Bécuwe, Philippe

doi:10.1016/j.freeradbiomed.2011.03.013

Cited by 31 publications

(34 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was decreased in DDB2-overexpressing cells because of the decrease in the nuclear translocation of the p65NF-kB protein, suggesting that this latter is not involved in DDB2-dependent induction of the IkBa gene. This explains also why DDB2 maintains a low expression of the MnSOD gene, by decreasing NF-kB binding to a kB site located in intron 2, as we showed recently (24).…”

Section: Mdasupporting

confidence: 62%

DDB2: A Novel Regulator of NF-κB and Breast Tumor Invasion

et al. 2013

Self Cite

View full text Add to dashboard Cite

The DNA repair protein damaged DNA-binding 2 (DDB2) has been implicated in promoting cell-cycle progression by regulating gene expression. DDB2 is selectively overexpressed in breast tumor cells that are noninvasive, but not in those that are invasive. We found that its overexpression in invasive human breast tumor cells limited their motility and invasiveness in vitro and blocked their ability to colonize lungs in vivo, defining a new function for DDB2 in malignant progression. DDB2 overexpression attenuated the activity of NF-kB and the expression of its target matrix metalloprotease 9 (MMP9). Mechanistic investigations indicated that DDB2 decreased NF-kB activity by upregulating expression of IkBa by binding the proximal promoter of this gene. This effect was causally linked to invasive capacity. Indeed, knockdown of DDB2-induced IkBa gene expression restored NF-kB activity and MMP9 expression, along with the invasive properties of breast tumor cells overexpressing DDB2. Taken together, our findings enlighten understanding of how breast cancer cells progress to an invasive phenotype and underscore potential clinical interest in DDB2 as a prognostic marker or therapeutic target in this setting. Cancer Res; 73(16); 5040-52. Ó2013 AACR.

show abstract

Section: Mdasupporting

confidence: 62%

DDB2: A Novel Regulator of NF-κB and Breast Tumor Invasion

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…Synthetic oleanane triterpenoids such as BAR are also potent inhibitors of the NF-jB inflammatory pathway through direct inhibition of IKKb kinase activity and indirectly through inducing an antioxidant response [26]. Previous studies have described that SOD2 expression is upregulated in aggressive BC via constitutive NFkB activation and it prevents the induction of a DNA damage response [29]. Here, we observed that BAR is anti-inflammatory and decreases the phosphorylation of p65 and expression of SOD2.…”

Section: Discussionsupporting

confidence: 51%

Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells

Refaat

Pararasa

Arif

et al. 2017

Free Radical Research

View full text Add to dashboard Cite

Bardoxolone-methyl (BAR) is reported to have anti-inflammatory, anti-proliferative and anti-fibrotic effects. BAR activates Nrf2 and may ameliorate oxidative stress through induction of antioxidant genes. However, off-target effects, probably concentration and NFkB-dependent, have limited the clinical use of BAR. Nrf2 regulates expression of antioxidant and mitochondrial genes and has been proposed as a target for both obesity and breast cancer. Therefore, we explored whether BAR can alter migration and proliferation in the MCF7 cell line and whether metabolic function is affected by BAR. Incubation with BAR caused a time-dependent migratory inhibition and an associated decrease in mitochondrial respiration. Both migratory and mitochondrial inhibition by BAR were further enhanced in the presence of fatty acids. In addition to the activation of Nrf2, BAR altered the expression of target mRNA GCLC and UCP1. After 24 h, BAR inhibited both glycolytic capacity, reserve (p < 0.05) and oxidative phosphorylation (p < 0.001) with an associated increase in mitochondrial ROS and loss of intracellular glutathione in MCF7 cells; however, impairment of mitochondrial activity was prevented by N-acetyl cysteine. The fatty acid, palmitate, increased mitochondrial ROS, impaired migration and oxidative phosphorylation but palmitate toxicity towards MCF7 could not be inhibited by N-acetyl cysteine suggesting that they exert effects through different pathways. BAR-activated AKT, induced DNA damage and inhibited cell proliferation. When the proteasome was inhibited, there was loss of BAR-mediated changes in p65 phosphorylation and SOD2 expression suggesting non-canonical NFkB signaling effects. These data suggest that BAR-induced ROS are important in inhibiting MCF7 migration and metabolism by negatively affecting glycolytic capacity and mitochondrial function. ARTICLE HISTORY

show abstract

“…On one hand, overexpression of MnSOD leads to growth retardation resulting from induction of cancer cell senescence (Plymate et al, 2003;Behrend et al, 2005) and apoptosis (Hurt et al, 2007); on the other hand, MnSOD levels appear to positively correlate with and contribute to enhanced metastatic behavior of certain types of cancer cells (Hempel et al, 2011). The most recent studies have shown increased levels of MnSOD expression in cancer cells of various tissue origins (Hu et al, 2005), positively correlating with aggressive or metastatic stages of cancers (Malafa et al, 2000;Ennen et al, 2011). Altered transcription factor profiles in cancer cells, such as aberrant activation of NFkB (Dhar et al, 2010;Holley et al, 2010), SP-1 (Dhar et al, 2010) and inactivation of p53 (Dhar et al, 2010), are suggested to be attributable to increases in MnSOD expression.…”

Section: /2mentioning

confidence: 99%

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Zhang

Wang

Liang

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

Cell migration is a dynamic process that is central to a variety of physiological functions as well as disease pathogenesis. The modulation of cell migration by p27 has been reported, but the exact mechanism(s) whereby p27 intersects with downstream effectors that control cell migration have not been elucidated. By systematically comparing p27+/+ MEFs with genetically ablated p27−/− MEFs using wound healing, transwell and time-lapse microscopic analyses, we provide direct evidence demonstrating that p27 inhibits both directional and random cell migration. Identical results were obtained with normal and cancer epithelial cells using complementary knockdown and overexpression approaches. Additional studies revealed that overexpression of manganese superoxide dismutase (MnSOD) and reduced intracellular oxidation played a key role in increased cell migration in p27-deficient cells. Furthermore, we identified signal transducer and activator of transcription 3 (STAT3) as the transcription factor responsible for p27-regulated MnSOD expression which was further mediated by ERKs/ATF1-dependent transactivation of CRE within the stat3 promoter. Collectively, our data strongly indicate that p27 plays a crucially negative role in cell migration by inhibiting MnSOD expression in a STAT-3 dependent manner.

show abstract

Regulation of the high basal expression of the manganese superoxide dismutase gene in aggressive breast cancer cells

Cited by 31 publications

References 25 publications

DDB2: A Novel Regulator of NF-κB and Breast Tumor Invasion

DDB2: A Novel Regulator of NF-κB and Breast Tumor Invasion

Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells

Loss of p27 upregulates MnSOD in a STAT3-dependent manner, disrupts intracellular redox activity and enhances cell migration

Contact Info

Product

Resources

About