Portal de Periódicos da CAPES

SRC family kinase (SFK) inhibition reduces rhabdomyosarcoma cell growth in vitro and in vivo and triggers p38 MAP kinase-mediated differentiation

2015; Impact Journals LLC; Volume: 6; Issue: 14 Linguagem: Inglês

10.18632/oncotarget.3043

1949-2553

Nadia Casini, Iris Maria Forte, Gianmarco Mastrogiovanni, Francesca Pentimalli, Adriano Angelucci, Claudio Festuccia, Valentina Tomei, Elisa Ceccherini, Domenico Di Marzo, Silvia Schenone, Maurizio Botta, Antonio Giordano, Paola Indovina,

RNA Research and Splicing

// Nadia Casini 1 , Iris Maria Forte 2 , Gianmarco Mastrogiovanni 1 , Francesca Pentimalli 2 , Adriano Angelucci 3 , Claudio Festuccia 3 , Valentina Tomei 1 , Elisa Ceccherini 1 , Domenico Di Marzo 2 , Silvia Schenone 4 , Maurizio Botta 5, 6 , Antonio Giordano 1, 2, 6 , Paola Indovina 1, 6 1 Department of Medicine, Surgery and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy 2 Oncology Research Center of Mercogliano (CROM), Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale”, IRCCS, Naples, Italy 3 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 4 Pharmacy Department, University of Genoa, Genoa, Italy 5 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy 6 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia PA, USA Correspondence to: Antonio Giordano, e-mail: giordano@temple.edu Paola Indovina, e-mail: pindovina@inwind.it Keywords: rhabdomyosarcoma, SRC family inhibition, NOTCH3, muscle differentiation, p38 MAPK, YES Received: August 01, 2014 Accepted: January 07, 2015 Published: February 03, 2015 ABSTRACT 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.