title: SYK is a target of lymphocyte-derived microparticles in the induction of apoptosis of human retinoblastoma cells.
abstract: Retinoblastoma (Rb) is an aggressive childhood cancer of the developing retina. This disease is associated with epigenetic deregulation of several cancer pathways including upregulation of the proto-oncogene spleen tyrosine kinase (SYK). We have previously demonstrated that lymphocyte-derived microparticles (LMPs) possess strong cytotoxic effect on cancer cells. This report demonstrated that LMPs have potent pro-apoptotic properties on human Rb cells, which was associated with a strong reduction of SYK expression. Perturbing SYK activity in Rb cells induced cell apoptosis and upregulated expression of p53 and p21. Interestingly, inhibition of p53 or knockdown of p21, abolished LMP-induced caspase-3 activity and cell death. Blocking oxidized phospholipid-rich LMPs with a specific antibody significantly prevented LMP-induced Rb apoptosis and reversed the expression patterns of SYK, p53, p21. In summary, our results suggest that LMPs are important pro-apoptotic regulators for Rb cells through reduction of SYK expression and upregulation of the p53-p21 pathway which ultimately activates caspase-3. These data may open unexpected avenues for the development of LMPs as a novel therapeutic strategy that would be particularly useful and relevant for the treatment of Rb.
authors.affiliation: Department of Pulmonology, Southwest Hospital, Third Military Medical University, Chongqing, China. qiuqian120@126.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Departments of Pediatrics, Hematology-Oncology and Pharmacology, University of Montréal, Montreal, QC, Canada. cyang_09@yahoo.com.
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Pulmonology, Southwest Hospital, Third Military Medical University, Chongqing, China. xiongwei64@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Departments of Pediatrics, Hematology-Oncology and Pharmacology, University of Montréal, Montreal, QC, Canada. houda.tahiri@umontreal.ca.
authors.forename: Houda
authors.initials: H
authors.lastname: Tahiri
authors.affiliation: Medical School, University of Montréal, Montreal, QC, Canada. Mathieu.payeur@hotmail.ca.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Payeur
authors.affiliation: Department of Ophthalmology, University of Montréal, Montreal, QC, Canada. rosanne.superstein@mcgill.ca.
authors.forename: Rosanne
authors.initials: R
authors.lastname: Superstein
authors.affiliation: Departments of Pediatrics, Hematology-Oncology and Pharmacology, University of Montréal, Montreal, QC, Canada. anne-sophie.carret@umontreal.ca.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Carret
authors.affiliation: Department of Ophthalmology, University of Montréal, Montreal, QC, Canada. patrick.hamel@umontreal.ca.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hamel
authors.affiliation: Department of Pathology and Cell Biology, University of Montréal, Montreal, QC, Canada. benjamin.ellezam@umontreal.ca.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ellezam
authors.affiliation: Departments of Pediatrics, Hematology-Oncology and Pharmacology, University of Montréal, Montreal, QC, Canada. Martin.Bussieres@crl.com.
authors.forename: Bussières
authors.initials: B
authors.lastname: Martin
authors.affiliation: Charles River Laboratories Preclinicals Services, Senneville, QC, Canada. mark.vezina@crl.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Vezina
authors.affiliation: Department of Ophthalmology, University of Montréal, Montreal, QC, Canada. mike.sapieha@umontreal.ca.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.affiliation: Department of Pulmonology, Southwest Hospital, Third Military Medical University, Chongqing, China. liuguoxiang2014@126.com.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Departments of Pediatrics, Hematology-Oncology and Pharmacology, University of Montréal, Montreal, QC, Canada. pierre.hardy@recherche-ste-justine.qc.ca.|Research Center of CHU Sainte-Justine, 3175 Côte-Sainte-Catherine, Room 2714, Montreal, QC, H3T 1C5, Canada. pierre.hardy@recherche-ste-justine.qc.ca.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hardy
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D012175:Retinoblastoma / Q000378:metabolism*; D000072377:Syk Kinase; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D053148:Caspase 3
keywords: Apoptosis; Lymphocyte-derived microparticles; Retinoblastoma; Spleen tyrosine kinase; p53–p21 pathway