Link between spermine oxidase and apoptosis antagonizing transcription factor: a new pathway in neuroblastoma

Neuroblastoma (NB) is a heterogeneous extra-cranial childhood type of cancer, responsible for approximately 15% of all paediatric cancer-related deaths. Although several critical genetic aberrations have been related to NB, only a few established molecular markers have been associated with prognosis [V-myc avian myelocytomatosis viral oncogene (MYCN) locus amplification, deletions of part of chromosome 1p, 11q23 and gain of 17q]. Regrettably, direct evidence of NB-related tumour suppressors or oncogenes has not been currently identified at these chromosomal regions. MYCNlocus amplification is present in approximately 20-30% of cases and is associated with a poor clinical outcome, representing the most important genetic prognostic marker. The functional guidelines for the prognosis of NB identify high-risk patients (<40% survival probabilities), but fail to identify patients at low and intermediate stages of the disease, which remains an issue to be resolved in NB. It has been shown that in NB cell lines and in a total-spermine oxidase (SMOX) transgenic mouse model, SMOX overexpression induces cellular stress via reactive oxygen species (ROS) imbalance. In this study, we demonstrated that the high expression level of the cytoprotective gene, apoptosis-antagonizing transcription factor (AATF), was driven by SMOX gene overexpression in both NB cells and Total-SMOX mice. The anti-apoptotic effect of AATF was supported by analysing the inhibition of the expression of the pro-apoptotic genes, BAX, BAK and PUMA, which were decreased, in both the in vitro and in vivo SMOX overexpressing model systems investigated. On the whole, this study supports the hypothesis that the SMOX gene can be considered as a novel anti-apoptotic marker in NB.