Activation of endogenous antioxidants as a common therapeutic strategy against cancer, neurodegeneration and cardiovascular diseases: A lesson learnt from DJ-1

Chan, Julie Y.H.; Chan, Samuel H.H.

doi:10.1016/j.pharmthera.2015.09.005

Cited by 68 publications

(48 citation statements)

References 102 publications

(104 reference statements)

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“…These changes in ratio imply that the mechanisms for regulating levels of ROS and DJ-1 are more complex than a simple direct relationship to mast cell accumulation and suggest that the underlying mechanisms change as mast cell burden increases. While diminished levels of the antioxidant DJ-1 are consistent with the increased ROS in ISM with lower tryptase values, the substantially elevated DJ-1 in association with more aggressive disease requires explanation, and the consequences of which would be to lessen ROS levels as disease progresses and thus promote survival of malignant cells [11]. …”

Section: Resultsmentioning

confidence: 99%

“…DJ-1 was originally described as an oncogene product [6] and its levels are elevated in a number of malignancies in correlation with poor prognosis [7–9]. The oncogenic activity of DJ-1 in part appears to relate to its ability to increase a cell's resistance to ROS [10, 11]. DJ-1 thus acts as a scavenger of ROS by undergoing oxidation during which it is degraded [7, 12–14], and by directly activating [15] or inducing transcription of other antioxidant enzymes [7, 16].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

et al. 2016

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Neoplastic accumulation of mast cells in systemic mastocytosis (SM) associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. Here, we examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. ROS levels were increased in both indolent (ISM) and aggressive variants of the disease (ASM). However, while DJ-1 levels were reduced in ISM with lower mast cell burden, they rose in ISM with higher mast cell burden and were significantly elevated in patients with ASM. Studies on mast cell lines revealed that activating KIT mutations induced constant ROS production and consequent DJ-1 oxidation and degradation that could explain the reduced levels of DJ-1 in the ISM population, while IL-6, a cytokine that increases with disease severity, caused a counteracting transcriptional induction of DJ-1 which would protect malignant mast cells from oxidative damage. A mouse model of mastocytosis recapitulated the biphasic changes in DJ-1 and the escalating IL-6, ROS and DJ-1 levels as mast cells accumulate, findings which were reversed with anti-IL-6 receptor blocking antibody. Our findings provide evidence of increased ROS and a biphasic regulation of the antioxidant DJ-1 in variants of SM and implicate IL-6 in DJ-1 induction and expansion of mast cells with KIT mutations. We propose consideration of IL-6 blockade as a potential adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels making mutation-positive mast cells vulnerable to oxidative damage.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

et al. 2016

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“…For example, Drosophila studies have found that DJ-1 suppresses PTEN activity, thereby promoting cell growth and promoting cellular defense against ROS through PI3K/Akt signaling (Chan and Chan, 2015). In vitro data demonstrates a direct interaction between DJ-1 and death domain-associated protein (Daxx) in the nucleus.…”

Section: Common Pathways In Pd Pathogenesismentioning

confidence: 99%

“…Strategies include targeting endogenous antioxidant enzymes and non-enzymatic antioxidant molecules. There are several endogenous antioxidant enzymes, including peroxidases, SOD, catalase, and thioredoxin, and non-enzymatic antioxidant molecules, such as GSH and uric acid (Chan and Chan, 2015). Screening for compounds that enhance endogenous antioxidant enzymatic activity or increase the production of endogenous antioxidants have been found to be neuroprotective in laboratory settings and have the potential to be therapeutically beneficial in treating PD.…”

Section: Therapeuticsmentioning

confidence: 99%

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Scott

Dawson

2017

Experimental Neurology

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Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Most PD cases are sporadic; however, rare familial forms have been identified. Autosomal recessive PD (ARPD) results from mutations in Parkin, PINK1, DJ-1, and ATP13A2, while rare, atypical juvenile ARPD result from mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and their function has revealed mitochondrial quality control, protein degradation processes, and oxidative stress responses as common pathways underlying PD pathogenesis. Understanding how aberrancy in these common processes leads to neurodegeneration has provided the field with numerous targets that may be therapeutically relevant to the development of disease-modifying treatments.

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“…Finally, previous work proposed that NaPB may trigger the activation of endogenous antioxidants and therefore provide neuroprotection [25]. Zhou et al [16] showed that NaPB treatment can upregulate DJ-1 expression levels in both C57BL/6 mice and the Thy1-Y39C αSyn mouse model of PD, which was further linked to neuroprotection and reduced disease progression [16].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by Epigenetic Modulation in a Transgenic Model of Multiple System Atrophy

et al. 2016

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Similar to Parkinson disease, multiple system atrophy (MSA) presents neuropathologically with nigral neuronal loss; however, the hallmark intracellular α-synuclein (αSyn) accumulation in MSA affects typically oligodendrocytes to form glial cytoplasmic inclusions. The underlying pathogenic mechanisms remain unclear. As MSA is predominantly sporadic, epigenetic mechanisms may play a role. We tested the effects of the pan-histone deacetylase inhibitor (HDACi) sodium phenylbutyrate in aged mice overexpressing αSyn under the control of the proteolipid protein promoter (PLP–αSyn) designed to model MSA and characterized by αSyn accumulation in oligodendrocytes and nigral neurodegeneration. HDACi improved motor behavior and survival of nigral neurons in PLP–αSyn mice. Furthermore, HDACi reduced the density of oligodendroglial αSyn aggregates, which correlated with the survival of nigral neurons in PLP–αSyn mice. For the first time, we suggest a role of HDACi in the pathogenesis of MSA-like neurodegeneration and support the future development of selective HDACi for MSA therapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-016-0447-1) contains supplementary material, which is available to authorized users.

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Activation of endogenous antioxidants as a common therapeutic strategy against cancer, neurodegeneration and cardiovascular diseases: A lesson learnt from DJ-1

Cited by 68 publications

References 102 publications

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes

Neuroprotection by Epigenetic Modulation in a Transgenic Model of Multiple System Atrophy

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