Abstract
ABSTRACTDrug-resistance to chemotherapics in aggressive neuroblastoma (NB) is characterized by enhanced cell survival mediated by TrkB and its ligand, brain-derived neurotrophic factor (BDNF); thus reduction in BDNF levels represent a promising strategy to overcome drug-resistance, but how chemotherapics regulate BDNF is unknown. Here, cisplatin treatment in SK-N-BE neuroblastoma upregulated multiple BDNF transcripts, except exons 5 and 8 variants. Cisplatin increased BDNF mRNA and protein, and enhanced translation of a firefly reporter gene flanked by BDNF 5′UTR exons 1, 2c, 4 or 6 and 3′UTR-long. To block BDNF translation we focused on aurora kinases inhibitors which are proposed as new chemotherapeutics. NB cell survival after 24 h treatment was 43% with cisplatin, and 22% by cisplatin+aurora kinase inhibitor PHA-680632, while the aurora kinases inhibitor alone was less effective; however the combined treatment induced a paradoxical increase of BDNF in surviving cells with strong translational activation of exon6-3′UTR-long transcript, while translation of BDNF transcripts 1, 2C and 4 was suppressed. In conclusion, combined cisplatin and aurora kinase inhibitor treatment increases cell death, but induces BDNF overproduction in surviving cells through an aurora kinase-independent mechanism.
Highlights
Neuroblastoma (NB) is a solid tumour derived from the sympathoadrenal lineage of the neural crest cells and is the most common paediatric tumour accounting for 15% of cancer-related death in children (Nakamura et al, 2014)
In this study we found that cisplatin-induced cytotoxic stress was able to stimulate brain-derived neurotrophic factor (BDNF) production in the MYCN-amplified neuroblastoma cell line SK-N-BE by enhancing both transcription and translation of multiple BDNF mRNAs
We further showed that the combined treatment with cisplatin and the aurora kinases inhibitor PHA-680632 was very effective in reducing cell survival from 43% with cisplatin alone to 22% with the combined treatment
Summary
Neuroblastoma (NB) is a solid tumour derived from the sympathoadrenal lineage of the neural crest cells and is the most common paediatric tumour accounting for 15% of cancer-related death in children (Nakamura et al, 2014). NBs can have either a favourable or an unfavourable prognosis depending on intrinsic features including the expression of neurotrophic factors of the neurotrophin family and their receptors, which are involved in cell survival and differentiation during development (Skaper, 2012; Brodeur et al, 2009). There is consolidated evidence that increased expression of BDNF and its receptor TrkB, working BDNF/ TrkB contributes to drug resistance and cell survival by increasing phosphorylation of AKT via the phosphatidylinositol 3′-kinase (PI3K)/AKT pathway (Ho et al, 2002), and the inhibition of PI3K restores cisplatin-induced cytotoxicity (Jaboin et al, 2003)
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