Toggle Main Menu Toggle Search

Open Access padlockePrints

MYCN sensitizes neuroblastoma to the MDM2-p53 antagonists Nutlin-3 and MI-63

Lookup NU author(s): Professor Deborah Tweddle, Professor John LunecORCiD


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


MYCN amplification is a major biomarker of poor prognosis, occurring in 25-30% of neuroblastomas. MYCN has contradictory roles in promoting cell growth and sensitizing cells to apoptosis. We have recently shown that p53 is a direct transcriptional target of MYCN in neuroblastoma and that p53-mediated apoptosis may be an important mechanism of MYCN-induced apoptosis. Although p53 mutations are rare in neuroblastoma at diagnosis, the p53/MDM2/p14(ARF) pathway is often inactivated through MDM2 amplification or p14(ARF) inactivation. We hypothesized that reactivation of p53 by inhibition of its negative regulator MDM2, using the MDM2-p53 antagonists Nutlin-3 and MI-63, will result in p53-mediated growth arrest and apoptosis especially in MYCN-amplified cells. Using the SHEP Tet21N MYCN-regulatable system, MYCN(-) cells were more resistant to both Nutlin-3 and MI-63 mediated growth inhibition and apoptosis compared with MYCN(+) cells and siRNA-mediated knockdown of MYCN in four MYCN-amplified cell lines resulted in decreased p53 expression and activation, as well as decreased levels of apoptosis following treatment with MDM2-p53 antagonists. In a panel of 18 neuroblastoma cell lines treated with Nutlin-3 and MI-63, the subset amplified for MYCN had a significantly lower mean GI(50) value (50% growth inhibition) and increased caspase 3/7 activity compared with the non-MYCN-amplified group of cell lines, but p53 mutant cell lines were resistant to the antagonists regardless of MYCN status. We conclude that amplification or overexpression of MYCN sensitizes neuroblastoma cell lines with wild-type p53 to MDM2-p53 antagonists and that these compounds may therefore be particularly effective in treating high-risk MYCN-amplified disease.

Publication metadata

Author(s): Gamble LD, Kees UR, Tweddle DA, Lunec J

Publication type: Article

Publication status: Published

Journal: Oncogene

Year: 2012

Volume: 31

Issue: 6

Pages: 752-763

Print publication date: 04/07/2011

ISSN (print): 0950-9232

ISSN (electronic): 1476-5594

Publisher: Nature Publishing Group


DOI: 10.1038/onc.2011.270

PubMed id: 21725357


Altmetrics provided by Altmetric