Urokinase activates macrophage PON2 gene transcription via the PI3K/ROS/MEK/SREBP-2 signalling cascade mediated by the PDGFR-β

Fuhrman, Bianca; Gantman, Anna; Khateeb, Jasmin; Volkova, Nina; Horke, Sven; Kiyan, Yulia; Dumler, Inna; Aviram, Michael

doi:10.1093/cvr/cvp184

Cited by 41 publications

(35 citation statements)

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“…However, one obvious difference is the level to which the two PONs are overexpressed in cancer tissues, as this was usually much higher for PON3. Little is known about regulatory pathways controlling PON2 and especially PON3 expression, with PON2 responding to AP-1/JNK signaling, 25 PI3K/PDGFR-b 26 and ER stress, 14 while differences exist in their response, for example, to oxidative stress 27 or high-fat, high cholesterol diet. 7 Expression of PON2 and PON3 in response to inflammatory mediators such as LPS, TNF-a, IFN-g or IL-1b remains somewhat controversial; 28,29 however, the expression did not appear to have a major impact on the systems tested.…”

Section: Discussionmentioning

confidence: 99%

PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death

et al. 2012

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To achieve malignancy, cancer cells convert numerous signaling pathways, with evasion from cell death being a characteristic hallmark. The cell death machinery represents an anti-cancer target demanding constant identification of tumor-specific signaling molecules. Control of mitochondrial radical formation, particularly superoxide interconnects cell death signals with appropriate mechanistic execution. Superoxide is potentially damaging, but also triggers mitochondrial cytochrome c release. While paraoxonase (PON) enzymes are known to protect against cardiovascular diseases, recent data revealed that PON2 attenuated mitochondrial radical formation and execution of cell death. Another family member, PON3, is poorly investigated. Using various cell culture systems and knockout mice, here we addressed its potential role in cancer. PON3 is found overexpressed in various human tumors and diminishes mitochondrial superoxide formation. It directly interacts with coenzyme Q10 and presumably acts by sequestering ubisemiquinone, leading to enhanced cell death resistance. Localized to the endoplasmic reticulum (ER) and mitochondria, PON3 abrogates apoptosis in response to DNA damage or intrinsic but not extrinsic stimulation. Moreover, PON3 impaired ER stress-induced apoptotic MAPK signaling and CHOP induction. Therefore, our study reveals the mechanism underlying PON3's anti-oxidative effect and demonstrates a previously unanticipated function in tumor cell development. We suggest PONs represent a novel class of enzymes crucially controlling mitochondrial radical generation and cell death. Cancer is one of the most life-threatening diseases and will remain a demanding issue in healthcare given the increase in life expectancy, constantly growing population and incidence of risk-factor acquiring patients. It is well established that several cellular deregulations are required for durable malignant transformation. Among them are sustained proliferation, replicative immortality, evasion of immune destruction and escape from cell death.1 Thus, tumor cells represent complex, broadly re-organized entities such that effective therapies demand tumor-specific identification of underlying mechanisms to reveal 'weak points'. Combinations of multiple targeting strategies with moderate compound concentrations are more promising and provoke less side-effects than highdose single treatment. Moreover, besides targeting the machinery directly involved in cell death execution, the preceding signaling pathways are attractive targets as these harbor critical upstream mediators with many of them understudied. Generally, redox signaling at the mitochondria is a vital pathway relevant to this concept in cancer research, as it controls both energy metabolism and regulation of cell death. Therefore, it is not surprising that mitochondrial dysfunction relates to a plethora of diseases and that many lead compounds are currently being developed in order to manipulate this organelle.2 Importantly, via generation of reactive oxygen species (ROS) or Ca...

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Section: Discussionmentioning

confidence: 99%

PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death

et al. 2012

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“…receptor-␤, 16,18 it is hard to predict which adaptor protein could possibly mediate the effect of uPA-uPAR interaction on PON1 expression in hepatocytes. This question will be pursued experimentally in future investigations.…”

Section: Discussionmentioning

confidence: 99%

“…We have demonstrated that in macrophages, uPA activates the NADPH oxidase complex, resulting in reactive oxygen species production, 15 and increases the expression of macrophage paraoxonase 2 (PON2), another member of the paraoxonase family. 16 We further hypothesize that uPA may promote oxidative stress in the arterial wall, also via modulation of PON1 activity. uPA is present in a variety of cells and is known to fulfill many functions through its biological activity, including intracellular signaling from the uPA/uPAR interaction.…”

mentioning

confidence: 83%

“…Incubation of HuH7 hepatocytes with uPA for 24 hours resulted in a significant increase in oxidative stress by 3.5-fold (see Supplemental Figure III). As reactive oxygen species are upstream activators of mitogen-activated protein kinase kinase (MEK) 1/2, and because uPA/uPAR interaction was shown to activate MEK/ extracellular signal-regulated kinase (ERK) signaling cascade, 11,16 we next examined whether uPA inhibits PON1 gene expression in a MEK-dependent manner.…”

Section: Upa Increases Cellular Oxidative Stress In Hepatocytesmentioning

confidence: 99%

“…Because uPA/uPAR interaction was shown to activate MEK/ ERK signaling cascade, 11,16 we examined whether uPA inhibits PON1 gene expression in a MEK-dependent manner. Treatment of HuH7 hepatocytes with uPA in the presence of PD98059, which is a selective MEK inhibitor, completely restored PON1 expression ( Figure 4A), suggesting that MEK is involved in uPA downregulation of hepatocyte PON1.…”

Section: Upa Inhibits Pon1 Gene Expression In a Mek-peroxisome Prolifmentioning

confidence: 99%

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Urokinase-Type Plasminogen Activator Downregulates Paraoxonase 1 Expression in Hepatocytes by Stimulating Peroxisome Proliferator–Activated Receptor-γ Nuclear Export

Khateeb

Kiyan²,

Aviram³

et al. 2012

ATVB

Self Cite

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Objective-The atherosclerotic lesion is characterized by lipid peroxide accumulation. Paraoxonase 1 (PON1) reduces atherosclerotic lesion oxidative stress, whereas urokinase-type plasminogen activator (uPA) increases oxidative stress in atherosclerotic lesions and contributes to the progression and complications of atherosclerosis. We hypothesized that uPA may promote oxidative stress in the arterial wall via modulation of PON1 activity. Because the liver is the main site for PON1 production, in the present study, we tested whether uPA influences PON1 expression in hepatocytes. Methods and Results-HuH7 hepatocytes were incubated in culture with increasing concentrations of uPA. uPA decreased PON1 gene expression and activity in a dose-dependent manner and accordingly suppressed PON1 secretion from hepatocytes. This effect required uPA/uPA receptor interaction. uPA downregulated PON1 gene expression via inactivation of peroxisome proliferator-activated receptor-␥ (PPAR␥) activity, and this effect was dependent on uPA-mediated mitogen-activated protein kinase kinase activation. Mechanistic studies showed that uPA enhanced mitogen-activated protein kinase kinase-PPAR␥ interaction, resulting in PPAR␥ nuclear export to the cytosol. Conclusion-This study provides the first evidence that uPA interferes with PPAR␥ transcriptional activity in hepatocytes, resulting in downregulation of PON1 expression and its secretion to the medium. This may explain, at least in part, the prooxidative effect of uPA in the vascular wall. Key Words: Hepatocytes Ⅲ PPAR␥ Ⅲ paraoxonase 1 (PON1) Ⅲ urokinase T he atherosclerotic lesion is dominated by accumulation of lipid peroxides, along with the progression of early plaque development. 1 Paraoxonase 1 (PON1) is a calciumdependent, high-density lipoprotein (HDL)-bound lipolactonase with antioxidative properties, which are associated with the enzyme's capability to decrease oxidative stress in atherosclerotic lesions 2 and to attenuate atherosclerosis development. Immunohistochemical analysis has revealed accumulation of PON1 in the human atherosclerotic lesion as it progresses from fatty streak to advanced lesion. 3 Recently, it was demonstrated that PON1 acts to reduce the oxidizing potency of lipids in atherosclerotic lesions, thus providing protection against oxidation. 4 Epidemiological evidence demonstrates that low PON1 activity is associated with increased risk of cardiovascular events and cardiovascular disease 5 and is an independent risk factor for coronary artery disease. 6 A primary determinant of serum PON1 levels is the availability of the enzyme for release by the liver, the principal site of PON1 production. 7 Urokinase-type plasminogen activator (uPA) is a serine protease enzyme of the fibrinolytic system, and uPA binding to its receptor (uPAR) is implicated in plasmin generation. The uPA/uPAR system has also a nonproteolytic role that extends beyond its role in fibrinolysis. 8 uPA is expressed in human atherosclerotic vessel wall, mainly in association with macrophages, 9 a...

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Dynamics of PDGFRβ expression in different cell types after brain injury

Kyyriäinen

Ndode-Ekane

Pitkänen

2016

Glia

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Platelet-derived growth factor receptor β (PDGFRβ) is upregulated after brain injury and its depletion results in the blood-brain barrier (BBB) damage. We investigated the time-window and localization of PDGFRβ expression in mice with intrahippocampal kainic acid-induced status epilepticus (SE) and in rats with lateral fluid-percussion-induced traumatic brain injury (TBI). Tissue immunohistochemistry was evaluated at several time-points after SE and TBI. The distribution of PDGFRβ was analyzed, and its cell type-specific expression was verified with double/triple-labeling of astrocytes (GFAP), NG2 cells, and endothelial cells (RECA-1). In normal mouse hippocampus, we found evenly distributed PDGFRβ+ parenchymal cells. In double-labeling, all NG2+ and 40%-60% GFAP+ cells were PDGFRβ+. After SE, PDGFRβ+ cells clustered in the ipsilateral hilus (178% of that in controls at fourth day, 225% at seventh day, P < 0.05) and in CA3 (201% at seventh day, P < 0.05), but the total number of PDGFRβ+ cells was not altered. As in controls, PDGFRβ-immunoreactivity was detected in parenchymal NG2+ and GFAP+ cells. We also observed PDGFRβ+ structural pericytes, detached reactive pericytes, and endothelial cells. After TBI, PDGFRβ+ cells clustered in the perilesional cortex and thalamus, particularly during the first post-injury week. PDGFRβ immunopositivity was observed in NG2+ and GFAP+ cells, structural pericytes, detached reactive pericytes, and endothelial cells. In some animals, PDGFRβ vascular staining was observed around the cortical glial scar for up to 3 months. Our data revealed an acute accumulation of PDGFRβ+ BBB-related cells in degenerating brain areas, which can be long lasting, suggesting an active role for PDGFRβ-signaling in blood vessel and post-injury tissue recovery. GLIA 2017;65:322-341.

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Urokinase activates macrophage PON2 gene transcription via the PI3K/ROS/MEK/SREBP-2 signalling cascade mediated by the PDGFR-β

Abstract: These findings provide a framework linking interactions among cellular signalling pathways associated with reactive oxygen species production, macrophage cholesterol biosynthesis, and cellular PON2 expression in vascular pathophysiology.

Cited by 41 publications

References 36 publications

PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death

PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death

Urokinase-Type Plasminogen Activator Downregulates Paraoxonase 1 Expression in Hepatocytes by Stimulating Peroxisome Proliferator–Activated Receptor-γ Nuclear Export

Dynamics of PDGFRβ expression in different cell types after brain injury

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