[HTML][HTML] Transmembrane adaptor protein PAG1 is a novel tumor suppressor in neuroblastoma

S Agarwal, R Ghosh, Z Chen, A Lakoma… - Oncotarget, 2016 - ncbi.nlm.nih.gov
Oncotarget, 2016ncbi.nlm.nih.gov
Abstract (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 …
Abstract
(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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