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

L. Raimondi, R. Ciarapica, M. De Salvo, F. Verginelli, M. Gueguen, C. Martini, L. De Sio, G. Cortese, M. Locatelli, T. P. Dang, N. Carlesso, L. Miele, S. Stifani, I. Limon, F. Locatelli, R. Rota

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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 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.

Original languageEnglish
Pages (from-to)871-881
Number of pages11
JournalCell Death and Differentiation
Volume19
Issue number5
DOIs
Publication statusPublished - May 2012

Fingerprint

Rhabdomyosarcoma
Cell Differentiation
Phosphorylation
Growth
Neoplasms
Down-Regulation
In Vitro Techniques
Notch Receptors
Phenotype
Myosin Heavy Chains
Muscle Development
Myoblasts
Differentiation Antigens
Skeletal Muscle Fibers
G1 Phase
Sarcoma
Skeletal Muscle
Pediatrics

Keywords

  • differentiation
  • muscle cells
  • Notch
  • rhabdomyosarcoma
  • sarcoma

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

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

In: Cell Death and Differentiation, Vol. 19, No. 5, 05.2012, p. 871-881.

Research output: Contribution to journalArticle

Raimondi, L, Ciarapica, R, De Salvo, M, Verginelli, F, Gueguen, M, Martini, C, De Sio, L, Cortese, G, Locatelli, M, Dang, TP, Carlesso, N, Miele, L, Stifani, S, Limon, I, Locatelli, F & Rota, R 2012, 'Inhibition of Notch3 signalling induces rhabdomyosarcoma cell differentiation promoting p38 phosphorylation and p21 Cip1 expression and hampers tumour cell growth in vitro and in vivo', Cell Death and Differentiation, vol. 19, no. 5, pp. 871-881. https://doi.org/10.1038/cdd.2011.171
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. / Inhibition of Notch3 signalling induces rhabdomyosarcoma cell differentiation promoting p38 phosphorylation and p21 Cip1 expression and hampers tumour cell growth in vitro and in vivo. In: Cell Death and Differentiation. 2012 ; Vol. 19, No. 5. pp. 871-881.
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AU - De Salvo, M.

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AU - Carlesso, N.

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