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Title: SRC family kinase (SFK) inhibition reduces rhabdomyosarcoma cell growth in vitro and in vivo and triggers p38 MAP kinase-mediated differentiation
Authors: Casini, Nadia
Forte, Iris Maria
Mastrogiovanni, Gianmarco
Pentimalli, Francesca
Angelucci, Adriano
Festuccia, Claudio
Tomei, Valentina
Ceccherini, Elisa
Di Marzo, Domenico
Schenone, Silvia
Botta, Maurizio 
Giordano, Antonio
Indovina, Paola
Keywords: NOTCH3; SRC family inhibition; YES; muscle differentiation; p38 MAPK; rhabdomyosarcoma; Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Differentiation; Cell Movement; Cell Proliferation; Cell Survival; Fluorescent Antibody Technique; Humans; Mice; Polymerase Chain Reaction; Pyrazoles; Pyrimidines; Rhabdomyosarcoma; Xenograft Model Antitumor Assays; p38 Mitogen-Activated Protein Kinases; src-Family Kinases
Issue Date: 2015
Project: None 
Recent data suggest that SRC family kinases (SFKs) could represent potential therapeutic targets for rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children. Here, we assessed the effect of a recently developed selective SFK inhibitor (a pyrazolo[3,4-d]pyrimidine derivative, called SI221) on RMS cell lines. SI221, which showed to be mainly effective against the SFK member YES, significantly reduced cell viability and induced apoptosis, without affecting non-tumor cells, such as primary human skin fibroblasts and differentiated C2C12 cells. Moreover, SI221 decreased in vitro cell migration and invasion and reduced tumor growth in a RMS xenograft model. SFK inhibition also induced muscle differentiation in RMS cells by affecting the NOTCH3 receptor-p38 mitogen-activated protein kinase (MAPK) axis, which regulates the balance between proliferation and differentiation. Overall, our findings suggest that SFK inhibition, besides reducing RMS cell growth and invasive potential, could also represent a differentiation therapeutic strategy for RMS.
ISSN: 1949-2553
DOI: 10.18632/oncotarget.3043
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