Characterisation of the p53 pathway in cell lines established from TH-MYCN transgenic mouse tumours

  • Authors:
    • Lindi Chen
    • Arman Esfandiari
    • William Reaves
    • Annette Vu
    • Michael D. Hogarty
    • John Lunec
    • Deborah A. Tweddle
  • View Affiliations

  • Published online on: January 31, 2018     https://doi.org/10.3892/ijo.2018.4261
  • Pages: 967-977
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Abstract

Cell lines established from the TH-MYCN transgenic murine model of neuroblastoma are a valuable preclinical, immunocompetent, syngeneic model of neuroblastoma, for which knowledge of their p53 pathway status is important. In this study, the Trp53 status and functional response to Nutlin-3 and ionising radiation (IR) were determined in 6 adherent TH-MYCN transgenic cell lines using Sanger sequencing, western blot analysis and flow cytometry. Sensitivity to structurally diverse MDM2 inhibitors (Nutlin-3, MI-63, RG7388 and NDD0005) was determined using XTT proliferation assays. In total, 2/6 cell lines were Trp53 homozygous mutant (NHO2A and 844MYCN+/+) and 1/6 (282MYCN+/-) was Trp53 heterozygous mutant. For 1/6 cell lines (NHO2A), DNA from the corresponding primary tumour was found to be Trp53 wt. In all cases, the presence of a mutation was consistent with aberrant p53 signalling in response to Nutlin-3 and IR. In comparison to TP53 wt human neuroblastoma cells, Trp53 wt murine control and TH-MYCN cell lines were significantly less sensitive to growth inhibition mediated by MI-63 and RG7388. These murine Trp53 wt and mutant TH-MYCN cell lines are useful syngeneic, immunocompetent neuroblastoma models, the former to test p53-dependent therapies in combination with immunotherapies, such as anti-GD2, and the latter as models of chemoresistant relapsed neuroblastoma when aberrations in the p53 pathway are more common. The spontaneous development of Trp53 mutations in 3 cell lines from TH-MYCN mice may have arisen from MYCN oncogenic driven and/or ex vivo selection. The identified species-dependent selectivity of MI-63 and RG7388 should be considered when interpreting in vivo toxicity studies of MDM2 inhibitors.
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March-2018
Volume 52 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Chen L, Esfandiari A, Reaves W, Vu A, Hogarty MD, Lunec J and Tweddle DA: Characterisation of the p53 pathway in cell lines established from TH-MYCN transgenic mouse tumours. Int J Oncol 52: 967-977, 2018
APA
Chen, L., Esfandiari, A., Reaves, W., Vu, A., Hogarty, M.D., Lunec, J., & Tweddle, D.A. (2018). Characterisation of the p53 pathway in cell lines established from TH-MYCN transgenic mouse tumours. International Journal of Oncology, 52, 967-977. https://doi.org/10.3892/ijo.2018.4261
MLA
Chen, L., Esfandiari, A., Reaves, W., Vu, A., Hogarty, M. D., Lunec, J., Tweddle, D. A."Characterisation of the p53 pathway in cell lines established from TH-MYCN transgenic mouse tumours". International Journal of Oncology 52.3 (2018): 967-977.
Chicago
Chen, L., Esfandiari, A., Reaves, W., Vu, A., Hogarty, M. D., Lunec, J., Tweddle, D. A."Characterisation of the p53 pathway in cell lines established from TH-MYCN transgenic mouse tumours". International Journal of Oncology 52, no. 3 (2018): 967-977. https://doi.org/10.3892/ijo.2018.4261