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Abstract
Cancer cells generate large amounts of lactate derived from glucose regardless of the available oxygen level. Cancer cells finely control ATP synthesis by modulating the uptake of substrates and the activity of enzymes involved in aerobic glycolysis (Warburg effect), which enables them to adapt to the tumor microenvironment. However, increasing evidence suggests that mitochondrial metabolism, including the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and glutaminolysis, is paradoxically activated in MYCN-amplified malignancies. Unlike non-amplified cells, MYCN-amplified cancer cells significantly promote OXPHOS-dependent ATP synthesis. Furthermore, tumor cells are differentially dependent on fatty acid β-oxidation (FAO) according to N-Myc status. Therefore, upregulation of FAO-associated enzymes is positively correlated with both N-Myc expression level and poor clinical outcome. This review explores therapeutic strategies targeting cancer stem-like cells for the treatment of tumors associated with MYCN amplification.
Highlights
Ren et al [31] reported that MYCN-amplified neuroblastoma cells prominently depend on ASCT2 to maintain sufficient level of glutamine to activate tricarboxylic acid (TCA) cycle
N-Myc contains a C-terminal basic region that can bind to DNA and a basic-helix-loop-helixleucine zipper domain that is responsible for the physical interaction with its counterpart MAX
N-Myc enables metabolic reprogramming of cancer cells, which cannot be explained by constitutive aerobic glycolysis (Warburg effect)
Summary
Ren et al [31] reported that MYCN-amplified neuroblastoma cells prominently depend on ASCT2 to maintain sufficient level of glutamine to activate TCA cycle. N-Myc activates GLDC transcription and is essential for maintaining high levels of GLDC expression in MYCN-amplified neuroblastoma cells, suggesting that GLDC and other SGOC pathway genes are cooperatively upregulated [38]. GLDC contributes to metabolic reprogramming exclusively in MYCN-amplified neuroblastoma cells, as demonstrated by the effect of GLDC knockdown on central carbon metabolism pathways, including glycolysis and the TCA cycle, as well as lipid synthesis.
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