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.
Highlights
Medulloblastoma (MB) is a common malignant paediatric brain tumour, developing in the posterior fossa of the brain and comprising 15–20% of paediatric tumours of the central nervous system (CNS) [1]
One strategy to overcome the effects of drug resistance caused by impaired p53 activation is to directly target downstream of p53, bypassing the need of its activation. p53 up-regulates a number of downstream targets, including pro-apoptotic genes to induce cell death
We first investigated if miR-34a was induced by etoposide in a range of MB cell lines previously used [29] and if this induction was correlated with induction of cell death
Summary
Medulloblastoma (MB) is a common malignant paediatric brain tumour, developing in the posterior fossa of the brain and comprising 15–20% of paediatric tumours of the central nervous system (CNS) [1]. MB arises from neural stem cells or granule-cell progenitors of the cerebellum and in around 30% of cases metastasises to other areas of the CNS via the cerebrospinal fluid. The current treatment for MB includes surgery, cranioradiotherapy and chemotherapy. Treatment is frequently associated with significant neuropsychological and physical disabilities [1,3] and chemotherapy remains the only treatment option available for younger patients following surgery. A related problem is chemoresistance, which has previously been reported in patients and MB cell lines [4,5,6,7]. It has been shown to be associated with altered drug metabolism [4,6] or genetic mutations affecting essential signalling pathways, such as NF-kappaB and/or p53 [7,8]
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