Mir-34a Mimics Are Potential Therapeutic Agents for p53-Mutated and Chemo-Resistant Brain Tumour Cells

Fan, Yuen Ngan, Meley, Daniel, Pizer, Barry and See, Violaine ORCID: 0000-0001-6384-8381 (2014) Mir-34a Mimics Are Potential Therapeutic Agents for p53-Mutated and Chemo-Resistant Brain Tumour Cells. PLoS ONE, 9 (9). e108514-.

Text Fan et al, 2014.pdf - Unspecified Download (2MB)

Abstract

Chemotherapeutic drug resistance and relapse remains a major challenge for paediatric (medulloblastoma) and adult (glioblastoma) brain tumour treatment. Medulloblastoma tumours and cell lines with mutations in the p53 signalling pathway have been shown to be specifically insensitive to DNA damaging agents. The aim of this study was to investigate the potential of triggering cell death in p53 mutated medulloblastoma cells by a direct activation of pro-death signalling downstream of p53 activation. Since non-coding microRNAs (miRNAs) have the ability to fine tune the expression of a variety of target genes, orchestrating multiple downstream effects, we hypothesised that triggering the expression of a p53 target miRNA could induce cell death in chemo-resistant cells. Treatment with etoposide, increased miR-34a levels in a p53-dependent fashion and the level of miR-34a transcription was correlated with the cell sensitivity to etoposide. miR-34a activity was validated by measuring the expression levels of one of its well described target: the NADH dependent sirtuin1 (SIRT1). Whilst drugs directly targeting SIRT1, were potent to trigger cell death at high concentrations only, introduction of synthetic miR-34a mimics was able to induce cell death in p53 mutated medulloblastoma and glioblastoma cell lines. Our results show that the need of a functional p53 signaling pathway can be bypassed by direct activation of miR-34a in brain tumour cells.

Item Type:	Article
Uncontrolled Keywords:	cell death, Medulloblastoma, cancer treatment, microRNAs, small interfering RNAs, apoptosis, MTS assay, chemotherapy
Depositing User:	Symplectic Admin
Date Deposited:	12 Mar 2015 10:21
Last Modified:	15 Dec 2022 16:44
DOI:	10.1371/journal.pone.0108514
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2008080