Induction of cyclooxygenase-2 expression by manganese in cultured astrocytes

Liao, Su‐Lan; Ou, Yen‐Chuan; Chen, Shih‐Yun; Chiang, An-Na; Chen, Chun‐Jung

doi:10.1016/j.neuint.2006.09.016

Cited by 45 publications

(40 citation statements)

References 75 publications

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“…Recent reports have shown that Akt, another upstream kinase, regulates COX-2 expression in various cells in culture and in animal studies (34,35). The significant decrease in TPAinduced COX-2 expression in female ICR mouse skin treated with LY294002 agrees with our previous study showing that pharmacologic inhibition of Akt abrogated TPAinduced COX-2 expression in male HR-1 hairless mouse skin (15).…”

Section: Discussionsupporting

confidence: 86%

Diallyl Trisulfide Inhibits Phorbol Ester–Induced Tumor Promotion, Activation of AP-1, and Expression of COX-2 in Mouse Skin by Blocking JNK and Akt Signaling

Shrotriya

Kundu

et al. 2010

Cancer Research

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An inverse relationship exists between the consumption of garlic and the risk of certain cancers. The present study was aimed at investigating the effect of garlic constituent diallyl trisulfide (DATS) on 12-Otetradecanoylphorbol-13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and to explore the underlying molecular mechanisms. Pretreatment of mouse skin with different garlic-derived allyl sulfides showed DATS to be the most potent in suppressing TPA-induced COX-2 expression. DATS significantly attenuated the DNA binding of activator protein-1 (AP-1), one of the transcription factors that regulate COX-2 expression, in TPA-stimulated mouse skin. DATS also diminished TPA-induced expression of c-Jun and c-Fos, the principal components of AP-1, and blunted the activation of c-Jun NH 2 -terminal kinase (JNK) and Akt. Pharmacologic inhibition of JNK or Akt by SP600125 or LY294002, respectively, resulted in diminished AP-1 DNA binding, reduced levels of c-Jun and c-Fos, and inhibition of COX-2 expression in TPA-treated mouse skin. The JNK or Akt kinase assay, taking c-Jun fusion protein as a substrate, revealed that TPA induced JNK-or Akt-mediated c-Jun phosphorylation in mouse skin, which was significantly attenuated by DATS or respective pharmacologic inhibitors. Evaluation of antitumor-promoting effect of DATS on 7,12-dimethylbenz(a)anthracene-initiated and TPA-promoted mouse skin carcinogenesis showed that pretreatment with DATS significantly reduced the incidence and multiplicity of papillomas. Taken together, the inhibitory effects of DATS on TPA-induced AP-1 activation and COX-2 expression through modulation of JNK or Akt signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis. Cancer Res; 70(5); 1932-40. ©2010 AACR.

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Section: Discussionsupporting

confidence: 86%

Diallyl Trisulfide Inhibits Phorbol Ester–Induced Tumor Promotion, Activation of AP-1, and Expression of COX-2 in Mouse Skin by Blocking JNK and Akt Signaling

Shrotriya

Kundu

et al. 2010

Cancer Research

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“…2). These findings are consistent with earlier observations of Mn(II)-induced PKC membrane translocation and activation (Liao et al, 2007).…”

Section: Discussionsupporting

confidence: 94%

“…At the histopathological level, manganism results in neurodegeneration and gliosis in the substantia nigra, the globus pallidus, and the striatum (Erikson and Aschner, 2003;Pal et al, 1999). Mn exposure causes membrane translocation and the subsequent activation of protein kinase C (PKC) (Liao et al, 2007), resulting in the downregulation of a number neurotransmitter transporters, including those for dopamine, norepinephrine, serotonin, GABA, glycine, and glutamate (Apparsundaram et al, 1998;Beckman et al, 1999;Fang et al, 2002;Gomeza et al, 1995;Melikian and Buckley, 1999;Zhang et al, 1997). Accordingly, we hypothesized that PKC signaling contributes to the Mn(II)-mediated disruption of astrocytic Gln carrier expression and function.…”

Section: Introductionmentioning

confidence: 98%

Disruption of astrocytic glutamine turnover by manganese is mediated by the protein kinase C pathway

Sidoryk‐Węgrzynowicz

Lee

et al. 2011

Glia

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Manganese (Mn) is a trace element essential for normal human development and is required for the proper functioning of a variety of physiological processes. Chronic exposure to Mn can cause manganism, a neurodegenerative disorder resembling idiopathic Parkinson's disease (PD). Mn(II) neurotoxicity is characterized by astrocytic impairment both in the expression and activity of glutamine (Gln) transporters. Because protein kinase C (PKC) activation leads to the downregulation of a number of neurotransmitter transporters and Mn(II) increases PKC activity, we hypothesized that the PKC signaling pathway contributes to the Mn(II)-mediated disruption of Gln turnover. Our results have shown that Mn exposure increases the phosphorylation of both the PKCα and PKCδ isoforms. PKC activity was also shown to be increased in response to Mn(II) treatment. Corroborating our earlier observations, Mn(II) also caused a decrease in Gln uptake. This effect was blocked by PKC inhibitors. Notably, PKC activation caused a decrease in Gln uptake mediated by systems ASC and N, but had no effect on the activities of systems A and L. Exposure to α-phorbol 12-myristate 13-acetate significantly decreased SNAT3 (system N) and ASCT2 (system ASC) protein levels. Additionally, a co-immunoprecipitation study demonstrated the association of SNAT3 and ASCT2 with the PKCδ isoform, and Western blotting revealed the Mn(II)-mediated activation of PKCδ by proteolytic cleavage. PKC activation was also found to increase SNAT3 and ubiquitin ligase Nedd4-2 binding and to induce hyperubiquitination. Taken together, these findings demonstrate that the Mn(II)-induced dysregulation of Gln homeostasis in astrocytes involves PKCδ signaling accompanied by an increase in ubiquitin-mediated proteolysis.

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“…It is important to state that the striatal cell types involved in the response to Mn intoxication were not determined; however, in vitro studies suggest that ERK, p38 MAPK and AKT contained into glial cells may be target to Mn modulation and mediate cell death or neuroinflammation. 67,68 The dashed circle shows GSK3b as a potential target for activated AKT. Noteworthy is that phosphorylation at Ser9 site of GSK3b by AKT causes inhibition of the enzyme and could be a neuroprotective event; however, a recent study that analyzed striatum from adult rats exposed in vivo and PC12 cells exposed in vitro to Mn indicated dephosphorylation and activation of GSK3b probably by the canonical Wnt pathway.…”

Section: Alteration In Mapk and Akt Signaling Induced By Manganesementioning

confidence: 99%

“…It is important to state that the striatal cell types involved in these Mn responses were not determined; however, in vitro studies in Mn-treated glial cells showed the participation of ERK1/2 and AKT in the expression of iNOS in microglia 67 and COX-2 in astrocytes. 68 In addition, it has been demonstrated that Mn produced apoptotic cell death via the ERK1/2 signaling pathway, with caspase-3 activation in PC12 cells. 60 Therefore, Mn-induced ERK1/2, p38 MAPK , and AKT activation may be associated with changes in neuroplasticity and/or cell viability in the immature rat striatum, thus disturbing and impairing neurophysiological functions and neurodevelopment.…”

Section: Alteration In Mapk and Akt Signaling Induced By Manganesementioning

confidence: 99%

Effect of Manganese on Signaling Pathways

Peres¹,

Córdova²,

Lopes³

et al. 2014

Manganese in Health and Disease

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A complex intercellular and intracellular signaling network modulates the main neural functions. Regulation of protein kinases and protein phosphatases activities modify the phosphorylation state of target proteins that direct a diversity of cell fates, including gene expression, neural cell migration, differentiation or proliferation, cell survival or death, and synaptic plasticity. Regardless of all these aspects, modulation of intracellular signaling pathways by toxicants has only recently become part of the molecular toxicology research. Manganese (Mn) exposure causes a neurological syndrome, manganism, which resembles Parkinson's disease. The mechanisms of Mn neurotoxicity are not completely clear but may involve mitochondrial dysfunctions, induction of oxidative stress, and alterations in dopaminergic system, especially in the basal ganglia. The modulation of intracellular cell signaling elements by Mn and the cell fates of these effects is an issue that requires attention. In this chapter, we will present cell signaling pathways dependent of protein kinases (e.g. PKA, PKC, MAPKs, AKT, and GSK3β) and protein phosphatases (e.g. PP1 and PP2A) that have been reported to be altered in response to Mn exposure. Since only a few studies have addressed these aspects in vivo, a series of data obtained in vitro from cell cultures exposed to Mn will also be presented, aiming to help us identify the possible sites of Mn action in cell signaling networks involved in the patophysiology of Mn neurotoxicity.

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Induction of cyclooxygenase-2 expression by manganese in cultured astrocytes

Cited by 45 publications

References 75 publications

Diallyl Trisulfide Inhibits Phorbol Ester–Induced Tumor Promotion, Activation of AP-1, and Expression of COX-2 in Mouse Skin by Blocking JNK and Akt Signaling

Diallyl Trisulfide Inhibits Phorbol Ester–Induced Tumor Promotion, Activation of AP-1, and Expression of COX-2 in Mouse Skin by Blocking JNK and Akt Signaling

Disruption of astrocytic glutamine turnover by manganese is mediated by the protein kinase C pathway

Effect of Manganese on Signaling Pathways

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