Inhibition of Notch3 signalling induces rhabdomyosarcoma cell differentiation promoting p38 phosphorylation and p21 super(Cip1) expression and hampers tumour cell growth in vitro and in vivo

Rhabdomyosarcoma (RMS) is a paediatric soft-tissue sarcoma arising from skeletal muscle precursors coexpressing markers of proliferation and differentiation. Inducers of myogenic differentiation suppress RMS tumourigenic phenotype. The Notch target gene HES1 is upregulated in RMS and prevents tumour...

Full description

Saved in:
Bibliographic Details
Published in:Cell death and differentiation 2012-05, Vol.19 (5), p.871-881
Main Authors: Raimondi, L, Ciarapica, R, De Salvo, M, Verginelli, F, Gueguen, M, Martini, C, De Sio, L, Cortese, G, Locatelli, M, Dang, T P, Carlesso, N, Miele, L, Stifani, S, Limon, I, Locatelli, F, Rota, R
Format: Article
Language:English
Subjects:
AKT protein
Cyclin-dependent kinase inhibitor p21
Data processing
Differentiation
G1 phase
Myoblasts
myogenesis
Myosin
Myotubes
Notch protein
Pediatrics
Phosphorylation
Rhabdomyosarcoma
Sarcoma
Skeletal muscle
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Rhabdomyosarcoma (RMS) is a paediatric soft-tissue sarcoma arising from skeletal muscle precursors coexpressing markers of proliferation and differentiation. Inducers of myogenic differentiation suppress RMS tumourigenic phenotype. The Notch target gene HES1 is upregulated in RMS and prevents tumour cell differentiation in a Notch-dependent manner. However, Notch receptors regulating this phenomenon are unknown. In agreement with data in RMS primary tumours, we show here that the Notch3 receptor is overexpressed in RMS cell lines versus normal myoblasts. Notch3-targeted downregulation in RMS cells induces hyper-phosphorylation of p38 and Akt essential for myogenesis, resulting in the differentiation of tumour cells into multinucleated myotubes expressing Myosin Heavy Chain. These phenomena are associated to a marked decrease in HES1 expression, an increase in p21 super(Cip1) level and the accumulation of RMS cells in the G1 phase. HES1-forced overexpression in RMS cells reverses, at least in part, the pro-differentiative effects of Notch3 downregulation. Notch3 depletion also reduces the tumourigenic potential of RMS cells both in vitro and in vivo. These results indicate that downregulation of Notch3 is sufficient to force RMS cells into completing a correct full myogenic program providing evidence that it contributes, partially through HES1 sustained expression, to their malignant phenotype. Moreover, they suggest Notch3 as a novel potential target in human RMS.
ISSN:1350-9047
DOI:10.1038/cdd.2011.171