Distinct effects on M2-type pyruvate kinase are involved in the dimethylsulfoxide-induced modulation of cellular proliferation and degranulation of mast cells

Koo, Na‐Youn; Kim, Kyeong-Man

doi:10.1007/s12272-009-2118-9

Cited by 4 publications

(2 citation statements)

References 29 publications

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“…Influence of dimethyl sulfoxide (DMSO) used as a solvent for agonists was also taken under consideration as it possesses various biological activities especially when applied intraperitoneally [ 18 ]. DMSO is able to activate ERK1/2 in vitro [ 33 , 34 ]. However, its relatively low dose of 0.022 g/kg (0.02 ml/kg), caused no significant effect on tumor growth when injected into WT animals and also did not change ERK1/2 status compared to WT control.…”

Section: Discussionmentioning

confidence: 99%

Specific Activation of A3, A2A and A1 Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration

et al. 2016

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CD73 (ecto-5'-nucleotidase), a cell surface enzyme hydrolyzing AMP to adenosine, was lately demonstrated to play a direct role in tumor progression including regulation of tumor vascularization. It was also shown to stimulate tumor macrophage infiltration. Interstitial adenosine, accumulating in solid tumors due to CD73 enzymatic activity, is recognized as a main mediator regulating the production of pro- and anti-angiogenic factors, but the engagement of specific adenosine receptors in tumor progression in vivo is still poorly researched. We have analyzed the role of high affinity adenosine receptors A1, A2A, and A3 in B16F10 melanoma progression using specific agonists (CCPA, CGS-21680 and IB-MECA, respectively). We limited endogenous extracellular adenosine background using CD73 knockout mice treated with CD73 chemical inhibitor, AOPCP (adenosine α,β-methylene 5’-diphosphate). Activation of any adenosine receptor significantly inhibited B16F10 melanoma growth but only at its early stage. At 14th day of growth, the decrease in tumor neovascularization and MAPK pathway activation induced by CD73 depletion was reversed by all agonists. Activation of A1AR primarily increased angiogenic activation measured by expression of VEGF-R2 on tumor blood vessels. However, mainly A3AR activation increased both the microvessel density and expression of pro-angiogenic factors. All agonists induced significant increase in macrophage tumor infiltration, with IB-MECA being most effective. This effect was accompanied by substantial changes in cytokines regulating macrophage polarization between pro-inflammatory and pro-angiogenic phenotype. Our results demonstrate an evidence that each of the analyzed receptors has a specific role in the stimulation of tumor angiogenesis and confirm significantly more multifaceted role of adenosine in its regulation than was already observed. They also reveal previously unexplored consequences to extracellular adenosine signaling depletion in recently proposed anti-CD73 cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Specific Activation of A3, A2A and A1 Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration

et al. 2016

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“…Also, as we have seen with inorganic arsenite 22 , absolute degranulation percentages (levels of antigen used) can affect levels of toxicant effects on RBL degranulation, so toxicant dose-responses should be done at several different antigen/ionophore concentrations. It is also important to consider the final concentration of DMSO vehicle when stimulating degranulation with ionophore, since degranulation is affected by DMSO 62 . We have found the DMSO concentrations used in this protocol do not affect degranulation, background readings, or 0.2% Triton X-100 values 2 .…”

Section: Discussionmentioning

confidence: 99%

A Microplate Assay to Assess Chemical Effects on RBL-2H3 Mast Cell Degranulation: Effects of Triclosan without Use of an Organic Solvent

Weatherly

Kennedy

Shim

et al. 2013

JoVE

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Mast cells play important roles in allergic disease and immune defense against parasites. Once activated (e.g. by an allergen), they degranulate, a process that results in the exocytosis of allergic mediators. Modulation of mast cell degranulation by drugs and toxicants may have positive or adverse effects on human health. Mast cell function has been dissected in detail with the use of rat basophilic leukemia mast cells (RBL-2H3), a widely accepted model of human mucosal mast cells [3][4][5] . Mast cell granule component and the allergic mediator β-hexosaminidase, which is released linearly in tandem with histamine from mast cells 6 , can easily and reliably be measured through reaction with a fluorogenic substrate, yielding measurable fluorescence intensity in a microplate assay that is amenable to high-throughput studies Triclosan is a broad-spectrum antibacterial agent that is present in many consumer products and has been found to be a therapeutic aid in human allergic skin disease [7][8][9][10][11] , although the mechanism for this effect is unknown. Here we demonstrate an assay for the effect of triclosan on mast cell degranulation. We recently showed that triclosan strongly affects mast cell function 2 . In an effort to avoid use of an organic solvent, triclosan is dissolved directly into aqueous buffer with heat and stirring, and resultant concentration is confirmed using UV-Vis spectrophotometry (using ε 280 = 4,200 L/M/cm) 12 . This protocol has the potential to be used with a variety of chemicals to determine their effects on mast cell degranulation, and more broadly, their allergic potential. Video LinkThe video component of this article can be found at

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A critical review of the role of M2PYK in the Warburg effect

Harris

Fenton

2019

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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It is becoming generally accepted in recent literature that the Warburg effect in cancer depends on inhibition of M 2 PYK, the pyruvate kinase isozyme most commonly expressed in tumors. We remain skeptical. There continues to be a general lack of solid experimental evidence for the underlying idea that a bottle neck in aerobic glycolysis at the level of M 2 PYK results in an expanded pool of glycolytic intermediates (which are thought to serve as building blocks necessary for proliferation and growth of cancer cells). If a bottle neck at M 2 PYK exists, then the remarkable increase in lactate production by cancer cells is a paradox, particularly since a high percentage of the carbons of lactate originate from glucose. The finding that pyruvate kinase activity is invariantly increased rather than decreased in cancer undermines the logic of the M 2 PYK bottle neck, but is consistent with high lactate production. The "inactive" state of M 2 PYK in cancer is often described as a dimer (with reduced substrate affinity) that has dissociated from an active tetramer of M 2 PYK. Although M 2 PYK clearly dissociates easier than other isozymes of pyruvate kinase, it is not clear that dissociation of the tetramer occurs in vivo when ligands are present that promote tetramer formation. Furthermore, it is also not clear whether the dissociated dimer retains any activity at all. A number of non-canonical functions for M 2 PYK have been proposed, all of which can be challenged by the finding that not all cancer cell types are dependent on M 2 PYK expression. Additional in-depth studies of the Warburg effect and specifically of the possible regulatory role of M 2 PYK in the Warburg effect are needed.

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Distinct effects on M2-type pyruvate kinase are involved in the dimethylsulfoxide-induced modulation of cellular proliferation and degranulation of mast cells

Cited by 4 publications

References 29 publications

Specific Activation of A3, A2A and A1 Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration

Specific Activation of A3, A2A and A1 Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration

A Microplate Assay to Assess Chemical Effects on RBL-2H3 Mast Cell Degranulation: Effects of Triclosan without Use of an Organic Solvent

A critical review of the role of M2PYK in the Warburg effect

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