Abstract 5347: Inhibition of Notch3 signaling reduces tumorigenic properties of human rhabdomyosarcoma cells

Medientyp: E-Artikel

Titel: Abstract 5347: Inhibition of Notch3 signaling reduces tumorigenic properties of human rhabdomyosarcoma cells

Beteiligte: Raimondi, Lavinia; Ciarapica, Roberta; Verginelli, Federica; Gueguen, Marie; Boldrini, Renata; De Sio, Luigi; Inserra, Alessandro; Cortese, Giancarlo; Locatelli, Mattia; Dang, Thao P.; Miele, Lucio; Stifani, Stefano; Limon, Isabelle; Locatelli, Franco; Rota, Rossella

Erschienen: American Association for Cancer Research (AACR), 2011

Sprache: Englisch

DOI: 10.1158/1538-7445.am2011-5347

ISSN: 0008-5472; 1538-7445

Schlagwörter: Cancer Research ; Oncology

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Beschreibung: Abstract Rhabdomyosarcoma is a soft tissue sarcoma of childhood arising from impaired developmental processes involving skeletal muscle progenitors. Notch signaling is strictly implicated in muscle tissue determination and has been reported to be abnormally activated in rhabdomyosarcoma. The expression of a dominant negative form of the Notch target gene HES1 or the inhibition of the γ-secretase has been shown to arrest rhabdomyosarcoma cell growth and trigger differentiation in vitro. Nevertheless, the mechanism underlying the deregulation of Notch signaling in rhabdomyosarcoma remains unclear. Here, we show that Notch3 and Notch1 are aberrantly activated in primary rhabdomyosarcomas and cell lines compared to skeletal muscle tissues or cultured myoblasts. In the present study we provide evidence that Notch3 targeted down-regulation restrains cell proliferation in both alveolar and embryonal subtypes of rhabdomyosarcoma cell lines. This phenomenon is paralleled by a transcriptional down-regulation of HES1 and an increase in both the cell cycle inhibitor p21cip1 and the under-phosphorylated pRb. Further, cells in which Notch3 has been silenced are capable to form differentiated multinucleated fibers showing de novo expression of late markers of myogenesis. In addition, down-regulation of Notch3 results in p38 and Akt hyper-phosphorylation and over-expression of PTEN. Finally, sustained silencing of Notch3 in rhabdomyosarcoma cells hampers their tumorigenic properties in vitro and in vivo. These results support a pathogenetic role for Notch3 in rhabdomyosarcoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5347. doi:10.1158/1538-7445.AM2011-5347

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