Silencing of peroxiredoxin 3 and peroxiredoxin 5 reveals the role of mitochondrial peroxiredoxins in the protection of human neuroblastoma SH-SY5Y cells toward MPP+

Simoni, Stéphanie De; Goemaere, Julie; Knoops, Bernard

doi:10.1016/j.neulet.2007.12.068

Cited by 85 publications

(67 citation statements)

References 30 publications

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“…Among the 37 DEGs in the pathway are COX10 and PRDX5 , both of which are downregulated by APE1 knockdown. COX10 has been shown to be essential for assembly and stability of the mitochondrial electron transport chain complexes I and IV (Diaz et al ., 2006), and loss of PRDX5 sensitizes the cell to apoptosis by complex I inhibitors (De Simoni et al ., 2008; Kropotov et al ., 2006). This opens up the potential of combining APE1‐based therapies and existing mitochondrial complex inhibitors as a novel approach to targeting cancer cells via inhibition of the mitochondrial dysfunction pathway.…”

Section: Discussionmentioning

confidence: 99%

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

et al. 2017

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Apurinic/apyrimidinic endonuclease 1/redox factor‐1 (APE1/Ref‐1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer‐related pathways. Because APE1 is essential for cell viability, generation of APE1‐knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single‐cell RNA sequencing to identify differentially expressed genes (DEGs) in relation to APE1 protein levels within the cell. Using a straightforward yet novel statistical design, we identified 2837 genes whose expression is significantly changed following APE1 knockdown. Using this gene expression profile, we identified multiple new pathways not previously linked to APE1, including the EIF2 signaling and mechanistic target of Rapamycin pathways and a number of mitochondrial‐related pathways. We demonstrate that APE1 has an effect on modifying gene expression up to a threshold of APE1 expression, demonstrating that it is not necessary to completely knockout APE1 in cells to accurately study APE1 function. We validated the findings using a selection of the DEGs along with siRNA knockdown and qRT‐PCR. Testing additional patient‐derived pancreatic cancer cells reveals particular genes (ITGA1,TNFAIP2,COMMD7,RAB3D) that respond to APE1 knockdown similarly across all the cell lines. Furthermore, we verified that the redox function of APE1 was responsible for driving gene expression of mitochondrial genes such as PRDX5 and genes that are important for proliferation such as SIPA1 and RAB3D by treating with APE1 redox‐specific inhibitor, APX3330. Our study identifies several novel genes and pathways affected by APE1, as well as tumor subtype specificity. These findings will allow for hypothesis‐driven approaches to generate combination therapies using, for example, APE1 inhibitor APX3330 with other approved FDA drugs in an innovative manner for pancreatic and other cancer treatments.

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Section: Discussionmentioning

confidence: 99%

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

et al. 2017

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“…The polyclonal rabbit Prdx5 antiserum was obtained as described previously (Wang et al, 2001). This antibody recognizes a 17-kDa protein in human nervous tissue and human SH-SY5Y neuroblastoma cell line (Lu et al, 2006;De Simoni et al, 2008) as it also does in mouse brain extract (Fig. 1).…”

Section: Materials and Methods Antibody Characterizationmentioning

confidence: 99%

“…Indeed, the abundance of Prdxs in different tissues, their high affinity for peroxides, and their distribution in all subcellular compartments account for their prominent role among the other well-characterized antioxidant enzymes such as superoxide dismutases, glutathione peroxidases, and catalase (Cox et al, 2010). The antioxidant cytoprotective function of Prdxs has been extensively studied in vitro (Manevich et al, 2002;Chang et al, 2004;Kim et al, 2008;De Simoni et al, 2008;Zhao et al, 2009). Also, studies on Prdx1-6 knockout or knockdown mice demonstrate that deficiency in any of the six isoforms leads to phenotypes highly related to increased levels of ROS/RNS (Neumann et al, 2003;Lee et al, 2003;Wang et al, 2004;Li et al, 2007;Iuchi et al, 2009;Yang et al, 2010).…”

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confidence: 99%

Peroxiredoxin distribution in the mouse brain with emphasis on neuronal populations affected in neurodegenerative disorders

Goemaere

Knoops

2011

J of Comparative Neurology

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Redox changes are observed in neurodegenerative diseases, ranging from increased levels of reactive oxygen/nitrogen species and disturbance of antioxidant systems, to nitro-oxidative damage. By reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides, peroxiredoxins (Prdxs) represent a major potential protective barrier against nitro-oxidative insults in the brain. While recent works have investigated the putative role of Prdxs in neurodegenerative disorders, less is known about their expression in the healthy brain. Here we used immunohistochemistry to map basal expression of Prdxs throughout C57BL/6 mouse brain. We first confirmed the neuronal localization of Prdx2-5 and the glial expression of Prdx1, Prdx4, and Prdx6. Then we performed an in-depth analysis of neuronal Prdx distribution in the brain. Our results show that Prdx2-5 are widely detected in the different neuronal populations, and especially well expressed in the olfactory bulb, in the cerebral cortex, in pons nuclei, in the red nucleus, in all cranial nerve nuclei, in the cerebellum, and in motor neurons of the spinal cord. In contrast, Prdx expression is very low in the dopaminergic neurons of substantia nigra pars compacta and in the CA1/2 pyramidal cells of hippocampus. This low basal expression may contribute to the vulnerability of these neurons to nitro-oxidative attacks occurring in Parkinson's disease and Alzheimer's disease. In addition, we found that Prdx expression levels are unevenly distributed among neurons of a determined region and that distinct regional patterns of expression are observed between isoforms, reinforcing the hypothesis of the nonredundant function of Prdxs.

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“…Using a polarographic method for real-time detection of H 2 O 2 , it was concluded that the removal of H 2 O 2 by energized brain mitochondria was largely dependent on the Trx/Prx system with a modest contribution by the GSH/GPx system (66). Prx3 and Prx5 are constitutively expressed in human neuroblastoma Sh-SY5Y cells, and their silencing by small hairpin RNAs renders the cells more susceptible to oxidative damage and apoptosis (63). Prx3 protects hippocampal neurons against excitotoxicity, and its up-regulation prevented or reduced gliosis, that is, proliferation of astrocytes in certain areas of the brain (96).…”

Section: Trx-based Systemsmentioning

confidence: 99%

Mitochondrial Energy Metabolism and Redox Signaling in Brain Aging and Neurodegeneration

Yin

Boveris²,

Cadenas³

2014

Antioxidants & Redox Signaling

214

166

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Significance: The mitochondrial energy-transducing capacity is essential for the maintenance of neuronal function, and the impairment of energy metabolism and redox homeostasis is a hallmark of brain aging, which is particularly accentuated in the early stages of neurodegenerative diseases. Recent Advances: The communications between mitochondria and the rest of the cell by energy-and redox-sensitive signaling establish a master regulatory device that controls cellular energy levels and the redox environment. Impairment of this regulatory devise is critical for aging and the early stages of neurodegenerative diseases. Critical Issues: This review focuses on a coordinated metabolic network-cytosolic signaling, transcriptional regulation, and mitochondrial function-that controls the cellular energy levels and redox status as well as factors which impair this metabolic network during brain aging and neurodegeneration. Future Directions: Characterization of mitochondrial function and mitochondria-cytosol communications will provide pivotal opportunities for identifying targets and developing new strategies aimed at restoring the mitochondrial energy-redox axis that is compromised in brain aging and neurodegeneration. Antioxid. Redox Signal. 20, 353-371.

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Silencing of peroxiredoxin 3 and peroxiredoxin 5 reveals the role of mitochondrial peroxiredoxins in the protection of human neuroblastoma SH-SY5Y cells toward MPP+

Cited by 85 publications

References 30 publications

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

APE1/Ref‐1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single‐cellRNAsequencing

Peroxiredoxin distribution in the mouse brain with emphasis on neuronal populations affected in neurodegenerative disorders

Mitochondrial Energy Metabolism and Redox Signaling in Brain Aging and Neurodegeneration

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