Beyond the Warburg Effect: N-Myc Contributes to Metabolic Reprogramming in Cancer Cells

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.

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

“…We also validated several of the top up- and downregulated genes mediated by TRIB2 overexpression in both untreated and BEZ235-treated cells ( Figure 1 D–G) by using RT-qPCR. The top genes were chosen from the list of differentially expressed genes ( Figure 1 C), from which we selected the 10 most upregulated and 10 most downregulated genes by TRIB2, as well as genes described to be involved in cancer proliferation and survival, namely Keratin 14 (KRT14), SRY-Box Transcription Factor 2 (SOX2), Formin-like protein 2 (FMNL2), BCL2-associated X, apoptosis regulator (BAX), TNF superfamily member 10 (TNFSF10), CEBPA, baculoviral IAP repeat-containing protein 7 (BIRC7), KiSS-1 metastasis suppressor (KISS1), Sestrin 2 (SESN2), MYCN Proto-Oncogene, BHLH Transcription Factor (MYCN) and BCL2 Binding Component 3 (PUMA) ( Figure 1 D–G) [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. KRT14, SOX2 and FMNL2 were upregulated by TRIB2 and downregulated by BEZ235 treatment, while BAX, TNFSF10 and CEBPA were downregulated by TRIB2 ( Figure 1 D).…”

The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells

“…The L-type amino acid transporter family is a crucial route of entry of EAAs into cancer cells and comprises four members (LAT1–4). Among the four LAT transporters, LAT1 is predominantly overexpressed in a variety of cancers [ 64 , 65 , 66 , 67 ]. LAT1 (SLC7A5) contains 12 transmembrane domains and covalently binds to CD98hc, which incorporates LAT1 into the cellular membrane, resulting in its functional expression [ 68 ].…”

“…LAT1 regulates the cellular uptake of exogenous leucine, thereby promoting mTORC1 activation in tumor cells [ 64 , 67 , 73 ]. Nutrient and growth factor pathways control cellular metabolism and protein synthesis by regulating mTORC1 activation [ 74 , 75 ].…”

Hydrogen Sulfide, an Endogenous Stimulator of Mitochondrial Function in Cancer Cells

“…According to the original version of the “Warburg hypothesis”, cancer cells switch to glycolysis from oxidative phosphorylation. However, more recent data indicate that many cancer cells, while upregulating glycolysis (as well as glutaminolysis, and many additional metabolic pathways) can also maintain or even increase their aerobic ATP generation via the stimulation of mitochondrial electron transport [ 101 , 102 , 103 , 104 , 105 , 106 ]. To anthropomorphize: maximizing ATP generation is the cancer cell’s primary “metabolic goal”: whatever biochemical mechanism serves this goal—even if it is ”wasteful” or perhaps useful in the short-term but detrimental in the longer-term—will be deemed ‘good enough’ to satisfy the “short-term thinking” of the cancer cell.…”