Energy metabolism in neuroblastoma and Wilms tumor

Abstract

To support high proliferation, the majority of cancer cells undergo fundamental metabolic changes such as increasing their glucose uptake and shifting to glycolysis for ATP production at the expense of far more efficient mitochondrial energy production by oxidative phosphorylation (OXPHOS), which at first glance is a paradox. This phenomenon is known as the Warburg effect. However, enhanced glycolysis is necessary to provide building blocks for anabolic growth. Apart from the generation of ATP, intermediates of glycolysis serve as precursors for a variety of biosynthetic pathways essential for cell proliferation. In the last 10-15 years the field of tumor metabolism has experienced an enormous boom in interest. It is now well established that tumor suppressor genes and oncogenes often play a central role in the regulation of cellular metabolism. Therefore, they significantly contribute to the manifestation of the Warburg effect. While much attention has focused on adult solid tumors, so far there has been comparatively little effort directed at elucidation of the mechanism responsible for the Warburg effect in childhood cancers. In this review we focus on metabolic pathways in neuroblastoma (NB) and Wilms tumor (WT), the two most frequent solid tumors in children. Both tumor types show alterations of the OXPHOS system and glycolytic features. Chromosomal alterations and activation of oncogenes like MYC or inactivation of tumor suppressor genes like TP53 can in part explain the changes of energy metabolism in these cancers. The strict dependence of cancer cells on glucose metabolism is a fairly common feature among otherwise biologically diverse types of cancer. Therefore, inhibition of glycolysis or starvation of cancer cells through glucose deprivation via a high-fat low-carbohydrate diet may be a promising avenue for future adjuvant therapeutic strategies.

Keywords: Cancer metabolism; Wilms tumor (WT); mitochondria; neuroblastoma (NB); oxidative phosphorylation (OXPHOS).

Figure 1

Some of the most common genetic abnormalities in NBs that affect different aspects of mitochondria such as morphology, respiratory chain function and metabolism. NBs frequently exhibit MYCN amplification, deletion of chromosome region 1p36, partial or complete loss of chromosome 11q, and gain of chromosome 17q. SDHB is located on chromosome region 1p36, SDHD on chromosome 11, both subunits of the OXPHOS complex II. Different studies have demonstrated various influences of N-Myc in correlation with other factors on mitochondrial or cytosolic metabolism in MYCN-amplified NBs. MYCN regulates gene expression and interacts with certain important factors determining the mode of energy generation (glycolysis vs. OXPHOS). SDHB/SDHD, succinate dehydrogenase subunit B/D; AHR, aryl hydrocarbon receptor; HIF, hypoxia inducible factor; MCT, monocarboxylate transporter; NB, neuroblastoma; OXPHOS, oxidative phosphorylation.