MYCN sensitizes human neuroblastoma to apoptosis by HIPK2 activation through a DNA damage response

Marialaura Petroni, Veronica Veschi, Andrea Prodosmo, Cinzia Rinaldo, Isabella Massimi, Maurizio Carbonari, Carlo Dominici, Heather P. McDowell, Christian Rinaldi, Isabella Screpanti, Luigi Frati, Armando Bartolazzi, Alberto Gulino, Silvia Soddu, Giuseppe Giannini

Research output: Contribution to journalArticle

Abstract

MYCN amplification occurs in approximately 20% of human neuroblastomas and is associated with early tumor progression and poor outcome, despite intensive multimodal treatment. However, MYCN overexpression also sensitizes neuroblastoma cells to apoptosis. Thus, uncovering the molecular mechanisms linking MYCN to apoptosis might contribute to designing more efficient therapies for MYCN-amplified tumors. Here we show that MYCN-dependent sensitization to apoptosis requires activation of p53 and its phosphorylation at serine 46. The p53S46 kinase HIPK2 accumulates on MYCN expression, and its depletion by RNA interference impairs p53S46 phosphorylation and apoptosis. Remarkably, MYCN induces a DNA damage response that accounts for the inhibition of HIPK2 degradation through an ATM- and NBS1-dependent pathway. Prompted by the rare occurrence of p53 mutations and by the broad expression of HIPK2 in our human neuroblastoma series, we evaluated the effects of the p53-reactivating compound Nutlin-3 on this pathway. At variance from other tumor histotypes, in MYCN-amplified neuroblastoma, Nutlin-3 further induced HIPK2 accumulation, p53S46 phosphorylation, and apoptosis, and in combination with clastogenic agents purged virtually the entire cell population. Altogether, our data uncover a novel mechanism linking MYCN to apoptosis that can be triggered by the p53-reactivating compound Nutlin-3, supporting its use in the most difficult-to-treat subset of neuroblastoma.

Original languageEnglish
Pages (from-to)67-77
Number of pages11
JournalMolecular Cancer Research
Volume9
Issue number1
DOIs
Publication statusPublished - Jan 2011

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ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Petroni, M., Veschi, V., Prodosmo, A., Rinaldo, C., Massimi, I., Carbonari, M., Dominici, C., McDowell, H. P., Rinaldi, C., Screpanti, I., Frati, L., Bartolazzi, A., Gulino, A., Soddu, S., & Giannini, G. (2011). MYCN sensitizes human neuroblastoma to apoptosis by HIPK2 activation through a DNA damage response. Molecular Cancer Research, 9(1), 67-77. https://doi.org/10.1158/1541-7786.MCR-10-0227