Abstract
Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation.
©2014 American Association for Cancer Research.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / immunology*
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Antineoplastic Agents / pharmacology*
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Antioxidants / pharmacology
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Cell Line, Tumor
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Cyclooxygenase 2 Inhibitors / immunology
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Cyclooxygenase 2 Inhibitors / pharmacology
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Female
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Glycerylphosphorylcholine / immunology
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Glycerylphosphorylcholine / metabolism
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Humans
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Melanoma, Experimental / drug therapy*
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Melanoma, Experimental / immunology*
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Mice
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Mice, Inbred C57BL
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Oxidative Stress / drug effects
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Oxidative Stress / immunology
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Platelet Activating Factor / agonists*
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Platelet Activating Factor / immunology
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Platelet Activating Factor / metabolism
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Platelet Membrane Glycoproteins / immunology
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Platelet Membrane Glycoproteins / metabolism
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Reactive Oxygen Species / immunology
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Reactive Oxygen Species / metabolism
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Receptors, G-Protein-Coupled / immunology
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction / drug effects
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Signal Transduction / immunology
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
Substances
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Antineoplastic Agents
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Antioxidants
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Cyclooxygenase 2 Inhibitors
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Platelet Activating Factor
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Platelet Membrane Glycoproteins
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Reactive Oxygen Species
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Receptors, G-Protein-Coupled
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platelet activating factor receptor
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Glycerylphosphorylcholine