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

Abstract

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. MYCN locus 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.

Mendelian randomization study of spermine oxidase and cancer risk

“…Since the SMOX genetic instrument, rs1741315, explained 5 to 6 times more variance of SMOX activity in newborns than in adults, we also tested the association between rs1741315 and neuroblastoma, a pediatric cancer in which SMOX has been reported to play a role 36,37 . Genetically lower levels of SMOX did not associate with lower risk of developing neuroblastoma 38 (OR=0.95; 95% CI:0.88, 1.03; P=0.182) (Table 2).…”

“…Spermine oxidase (SMOX), a member of the mammalian polyamine catabolic pathway, encodes an enzyme with cytoplasmic and nuclear expression in most tissues 42 , that catalyzes the oxidation of spermine to spermidine with the production of hydrogen peroxide (H 2 O 2 ) and 3-aminopropanal (3-AP) 10–11 . SMOX has been reported as a source of induced reactive oxygen species (ROS) associated with neuroblastoma, gastric, lung, breast, prostate and colon cancers 12–16,36,37 , implying that inhibition of SMOX could be a target for chemoprevention 3 . However, so far, studies of SMOX inhibition have been observational in their nature with no direct inference on causation 12–16,36,37 .…”

“…SMOX has been reported as a source of induced reactive oxygen species (ROS) associated with neuroblastoma, gastric, lung, breast, prostate and colon cancers 12–16,36,37 , implying that inhibition of SMOX could be a target for chemoprevention 3 . However, so far, studies of SMOX inhibition have been observational in their nature with no direct inference on causation 12–16,36,37 . Genome-wide association studies (GWAS) of SMOX activity are also lacking.…”

Biochemical and pathophysiological properties of polyamines

“…Their accumulation at high extracellular concentrations or deregulation of the systems that control polyamine homeostasis can induce programmed cell death (or apoptosis) in various cell types. The polyamines spermidine and spermine are substrates for several enzymes that generate cytotoxic metabolites, via the action of monoamine oxidase (MAO), polyamine oxidase (PAO), spermine oxidase (SMOX), or copper amine oxidases (CuAOs) (Ohkubo et al 2019;Fratini et al 2019;Agostinelli et al 2014). Amine oxidases (AOs) regulate the levels of these polycations.…”

“…Interestingly, spermine oxidase (SMOX), a FAD-containing enzyme, specifically oxidizes spermine (Spm) and its dysregulation alters polyamine homeostasis, leading to aetiology of several pathological conditions, including cancer (Casero and Pegg 2010). Direct mechanistic links between inflammation, SMOX activity, ROS production, and carcinogenesis have been demonstrated (Goodwin et al 2008;Fratini et al 2019). Main biochemical, cellular, and physiological processes in which SMOX is involved have been highlighted (Cervelli et al 2012).…”