Oncotarget

Research Papers:

Transmembrane adaptor protein PAG1 is a novel tumor suppressor in neuroblastoma

Saurabh Agarwal, Rajib Ghosh, Zaowen Chen, Anna Lakoma, Preethi H. Gunaratne, Eugene S. Kim and Jason M. Shohet _

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Oncotarget. 2016; 7:24018-24026. https://doi.org/10.18632/oncotarget.8116

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Abstract

Saurabh Agarwal1,*, Rajib Ghosh2,*, Zaowen Chen1, Anna Lakoma3, Preethi H. Gunaratne2, Eugene S. Kim3,4, Jason M. Shohet1

1Department 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

2Department of Biology & Biochemistry, University of Houston, Houston, Texas 77204, USA

3Michael E. DeBakey, Department of Surgery, Division of Pediatric Surgery, Baylor College of Medicine, Houston, Texas 77030, USA

4Department of Surgery, Division of Pediatric Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA

*SA and RG are co-first authors

Correspondence to:

Jason M. Shohet, e-mail: jmshohet@txch.org

Keywords: neuroblastoma, Src, PAG1, tumor suppressor

Received: September 29, 2015    Accepted: March 01, 2016    Published: March 16, 2016

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.


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