title: Transmembrane adaptor protein PAG1 is a novel tumor suppressor in neuroblastoma.
abstract: Neuroblastoma (NB) is the most common extracranial pediatric solid tumor with high mortality rates. The tyrosine kinase c-Src has been known to play an important role in differentiation of NB cells, but the mechanism of c-Src regulation has not been defined. Here, we characterize PAG1 (Cbp, Csk binding protein), a central inhibitor of c-Src and other Src family kinases, as a novel tumor suppressor in NB. Clinical cohort analysis demonstrate that low expression of PAG1 is a significant prognostic factor for high stage disease, increased relapse, and worse overall survival for children with NB. PAG1 knockdown in NB cells promotes proliferation and anchorage-independent colony formation with increased activation of AKT and ERK downstream of c-Src, while PAG1 overexpression significantly rescues these effects. In vivo, PAG1 overexpression significantly inhibits NB tumorigenicity in an orthotopic xenograft model. Our results establish PAG1 as a potent tumor suppressor in NB by inhibiting c-Src and downstream effector pathways. Thus, reactivation of PAG1 and inhibition of c-Src kinase activity represents an important novel therapeutic approach for high-risk NB.
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Department of Biology & Biochemistry, University of Houston, Houston, Texas 77204, USA.
authors.forename: Rajib
authors.initials: R
authors.lastname: Ghosh
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Zaowen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Michael E. DeBakey, Department of Surgery, Division of Pediatric Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Lakoma
authors.affiliation: Department of Biology & Biochemistry, University of Houston, Houston, Texas 77204, USA.
authors.forename: Preethi H
authors.initials: PH
authors.lastname: Gunaratne
authors.affiliation: Michael E. DeBakey, Department of Surgery, Division of Pediatric Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Surgery, Division of Pediatric Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA.
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Shohet
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002648:Child; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C498710:PAG1 protein, human
keywords: PAG1; Src; neuroblastoma; tumor suppressor