title: Syk is a novel target of arsenic trioxide (ATO) and is involved in the toxic effect of ATO in human neutrophils.
abstract: The anticancer dug arsenic trioxide (ATO) is known to be toxic for human mononuclear and neutrophil cell populations by a mechanism that needs to be further investigated. Due to the well-characterized role of Syk kinase in phagocytosis and because activation and involvement of Syk in response to ATO treatment has never been reported in any cells, we decided to determine whether or not Syk is involved in the mode of action of ATO. Human neutrophils were freshly isolated and incubated in vitro with ATO and the role of Syk was evaluated in different neutrophil functions. We found that ATO increased phosphorylation of Syk and this was reversed by piceatannol, a Syk-specific pharmacological inhibitor. In addition, ATO increased the phagocytic ability of neutrophils and degranulation via Syk activation. Finally, using both pharmacological inhibition and cellular depletion of Syk via an antisense approach, we found that this kinase is involved in apoptosis. We conclude that Syk activation is an important step in the mode of action of ATO in mature immune cells such as neutrophils and is involved in rapid, intermediate and lengthy biological processes. This is the first study to report that Syk is activated by ATO.
authors.affiliation: Laboratoire de Recherche en Inflammation et Physiologie des Granulocytes, Université du Québec, INRS-Institut Armand-Frappier, Laval, QC, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Antoine
authors.forename: Jamila
authors.initials: J
authors.lastname: Ennaciri
authors.forename: Denis
authors.initials: D
authors.lastname: Girard
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002448:Cell Adhesion / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002469:Cell Separation; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D008565:Membrane Proteins / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010087:Oxides / Q000633:toxicity*; D010587:Phagocytosis / Q000187:drug effects; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013154:Spleen / Q000187:drug effects* / Q000201:enzymology*; D013267:Stilbenes / Q000494:pharmacology; D000072377:Syk Kinase
chemical_list: D000970:Antineoplastic Agents; D016375:Antisense Elements (Genetics); D001152:Arsenicals; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010087:Oxides; D013267:Stilbenes; C041525:3,3',4,5'-tetrahydroxystilbene; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D000077237:Arsenic Trioxide