Modulation of chemotherapeutic drug resistance in neuroblastoma SK-N-AS cells by the neural apoptosis inhibitory protein and miR-520f

Harry Harvey, Olga Piskareva, Laura Creevey, Leah C. Alcock, Patrick G. Buckley, Maureen J. O'Sullivan, Miguel F. Segura, Soledad Gallego, Raymond L. Stallings, Isabella M. Bray

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19 Citations (Scopus)

Abstract

© 2014 UICC. The acquisition of multidrug resistance is a major impediment to the successful treatment of neuroblastoma, a clinically heterogeneous cancer accounting for ∼15% of all pediatric cancer deaths. The MYCN transcription factor, whose gene is amplified in ∼30% of high-risk neuroblastoma cases, influences drug resistance by regulating a cadre of genes, including those involved with drug efflux, however, other high-risk subtypes of neuroblastoma lacking MYCN amplification, such as those with chromosome 11q deletions, also acquire multidrug resistance. To elucidate additional mechanisms involved with drug resistance in non-MYCN amplified tumour cells, an SK-N-AS subline (SK-N-AsCis24) that is significantly resistant to cisplatin and cross resistant to etoposide was developed through a pulse-selection process. High resolution aCGH analysis of SK-N-AsCis24 revealed a focal gain on chromosome 5 containing the coding sequence for the neural apoptosis inhibitory protein (NAIP). Significant overexpression of NAIP mRNA and protein was documented, while experimental modulation of NAIP levels in both SK-N-AsCis24 and in parental SK-N-AS cells confirmed that NAIP was responsible for the drug resistant phenotype by apoptosis inhibition. Furthermore, a decrease in the NAIP targeting microRNA, miR-520f, was also demonstrated to be partially responsible for increased NAIP levels in SK-N-AsCis24. Interestingly, miR-520f levels were determined to be significantly lower in post-chemotherapy treatment tumours relative to matched prechemotherapy samples, consistent with a role for this miRNA in the acquisition of drug resistance in vivo, potentially through decreased NAIP targeting. Our findings provide biological novel insight into neuroblastoma drug-resistance and have implications for future therapeutic research.
Original languageEnglish
Pages (from-to)1579-1588
JournalInternational Journal of Cancer
Volume136
Issue number7
DOIs
Publication statusPublished - 1 Apr 2015

Keywords

  • Cisplatin
  • Drug-resistance
  • miR-520f
  • NAIP
  • Neuroblastoma

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    Harvey, H., Piskareva, O., Creevey, L., Alcock, L. C., Buckley, P. G., O'Sullivan, M. J., Segura, M. F., Gallego, S., Stallings, R. L., & Bray, I. M. (2015). Modulation of chemotherapeutic drug resistance in neuroblastoma SK-N-AS cells by the neural apoptosis inhibitory protein and miR-520f. International Journal of Cancer, 136(7), 1579-1588. https://doi.org/10.1002/ijc.29144