MYCN is a member of the MYC family of proto-oncogenes. It encodes a transcription factor, MYCN, involved in the control of fundamental processes during embryonal development. The MYCN protein is situated downstream of several signaling pathways promoting cell growth, proliferation and metabolism of progenitor cells in different developing organs and tissues. Conversely, deregulated MYCN signaling supports the development of several different tumors, mainly with a childhood onset, including neuroblastoma, medulloblastoma, rhabdomyosarcoma and Wilms’ tumor, but it is also associated with some cancers occurring during adulthood such as prostate and lung cancer. In neuroblastoma, MYCN-amplification is the most consistent genetic aberration associated with poor prognosis and treatment failure. Targeting MYCN has been proposed as a therapeutic strategy for the treatment of these tumors and great efforts have allowed the development of direct and indirect MYCN inhibitors with potential clinical use.

During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy.

SummaryIn pediatric neuroblastoma, MYCN-amplification correlates to poor clinical outcome and new treatment options are needed for these patients. Identifying the metabolic adaptations crucial for tumor progression may be a promising strategy to discover novel therapeutic targets. Here, we have combined proteomics, gene expression profiling, functional analysis, and metabolic tracing to decipher the impact of MYCN on neuroblastoma cell metabolism. We found that high MYCN levels are correlated with altered expression of proteins involved in multiple metabolic processes, including enhanced glycolysis and increased oxidative phosphorylation. Unexpectedly, we discovered that MYCN-amplified cells showed de novo glutamine synthesis. Furthermore, inhibition of β-oxidation reduced the viability of MYCN-amplified cells in vitro and decreased tumor burden in vivo, while not affecting non-MYCN–amplified tumors. Our data provide information on metabolic processes in MYCN expressing tumors, which could be exploited for the development of novel targeted therapies.

Histamine, serotonin and dopamine are biogenic amines involved in intercellular communication with multiple effects on human pathophysiology. They are products of two highly homologous enzymes, histidine decarboxylase and L-aromatic amino acid decarboxylase, and transmit their signals through different receptors and signal transduction mechanisms. Polyamines derived from ornithine (putrescine, spermidine and spermine) are mainly involved in intracellular effects related to cell proliferation and death mechanisms. This review summarizes structural and functional evidence for interactions between components of all these amine metabolic and signalling networks (decarboxylases, transporters, oxidases, receptors etc.) at cellular and tissue levels, distinct from nervous and neuroendocrine systems, where the crosstalk among these amine-related components can also have important pathophysiological consequences. The discussion highlights aspects that could help to predict and discuss the effects of intervention strategies. LINKED ARTICLESThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 Abbreviations CYP, cytochrome P450; DAO, diamine oxidase; DDC, dopamine decarboxylase; DFMO, difluoromethyl ornithine; HDC, histidine decarboxylase; MATE1, multidrug and toxin extrusion transporter-1; ODC, ornithine decarboxylase; SAM, S-adenosyl methionine; sVMATs, vesicular monoamine transporters The aim of the present reviewIntegration of biological information can reveal new properties and features that could contribute to progress in the characterization of complex systems; this is a fundamental principle of systems biology (Kitano, 2002). A human being can be considered as a system composed of different subsystems specialized in certain functions: interchange with the environment, defence, internal coordination (metabolic homeostasis, motor and cognitive capacities) and reproduction.Biogenic amines and polyamines have relevant roles in all of these human functions, but the topic is too extensive to be the subject of a single review. Excellent reviews have been published recently on the pharmacological potential of biogenic amines (and related compounds) in neurotransmission (Nuutinen and Panula, 2010;Lin et al., 2011;Lodge and Grace, 2011;Sharp and Cowen, 2011;Tiligada et al., 2011;Deneris and Wyler, 2012;Fleck et al., 2012; and others within this volume).In the present work, we focus our attention on a set of small physiological subsystems beyond neurotransmission, where components related to cationic amino acids, dopamine and serotonin are present and can interact ( Figure 1). Here, we also discuss the potential consequences of these metabolic connections for pharmacology, as well as pointing out some important gaps of information that require further basic research in order to generate useful translational information. General biochemical and physiological features of biogenic amines and polyaminesBiogenic amines ...

Background: Polyamine metabolism is relevant in neuroblastoma progression. Results: Polyamine synthesis is hampered by glycolysis inhibition in neuroblastoma cells. Conclusion: Glycolysis inhibition triggers signaling events leading to decrease of N-Myc and ODC levels, resulting in decreased polyamine synthesis. Significance: Combined therapies targeting glucose metabolism and polyamine synthesis could be effective in the treatment of n-myc-expressing tumors.