title: Combined cisplatin and aurora inhibitor treatment increase neuroblastoma cell death but surviving cells overproduce BDNF.
abstract: Drug-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.
authors.affiliation: University of Trieste, Department of Life Sciences, Trieste 34127, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Polacchini
authors.affiliation: University of Trieste, Department of Life Sciences, Trieste 34127, Italy Nerviano Medical Sciences, Nerviano, Milano 20014, Italy Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova 16163, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Albani
authors.affiliation: University of Trieste, Department of Life Sciences, Trieste 34127, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Baj
authors.affiliation: University of Trieste, Department of Life Sciences, Trieste 34127, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Colliva
authors.affiliation: Nerviano Medical Sciences, Nerviano, Milano 20014, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Carpinelli
authors.affiliation: University of Trieste, Department of Life Sciences, Trieste 34127, Italy tongi@units.it.
authors.forename: Enrico
authors.identifier: http://orcid.org/0000-0003-0485-0603
authors.initials: E
authors.lastname: Tongiorgi
keywords: Aurora kinase; Cisplatin; Drug resistance; Neuroblastoma; Neurotrophins; PHA-680632