Signaling Pathways Regulating Redox Balance in Cancer Metabolism

Abstract

The interplay between rewiring tumor metabolism and oncogenic driver mutations is only beginning to be appreciated. Metabolic deregulation has been described for decades as a bystander effect of genomic aberrations. However, for the biology of malignant cells, metabolic reprogramming is essential to tackle a harsh environment, including nutrient deprivation, reactive oxygen species production, and oxygen withdrawal. Besides the well-investigated glycolytic metabolism, it is emerging that several other metabolic fluxes are relevant for tumorigenesis in supporting redox balance, most notably pentose phosphate pathway, folate, and mitochondrial metabolism. The relationship between metabolic rewiring and mutant genes is still unclear and, therefore, we will discuss how metabolic needs and oncogene mutations influence each other to satisfy cancer cells' demands. Mutations in oncogenes, i.e., PI3K/AKT/mTOR, RAS pathway, and MYC, and tumor suppressors, i.e., p53 and liver kinase B1, result in metabolic flexibility and may influence response to therapy. Since metabolic rewiring is shaped by oncogenic driver mutations, understanding how specific alterations in signaling pathways affect different metabolic fluxes will be instrumental for the development of novel targeted therapies. In the era of personalized medicine, the combination of driver mutations, metabolite levels, and tissue of origins will pave the way to innovative therapeutic interventions.

Keywords: OXPHOS; metabolic reprogramming; oncometabolites; one-carbon metabolism; pentose phosphate pathway.

Figure 1

One-carbon metabolism (1-CM) and pentose phosphate pathway (PPP) at the cross-road between anabolism and redox balance. Simplified scheme of the crosstalk between metabolic and signaling pathways that can occur in cancer cells. Pro-tumorigenic signals are represented in red and anti-tumorigenic in green. Glycolysis regulates both PPP and 1-CM. Serine signaling pathway, once PKM2 activity is inhibited (red light), leads to glycolytic intermediates accumulation hence fueling both PPP and 1-CM. Serine metabolism enzymes bridge the shunt between glycolysis and 1-CM, with specific oncogene upregulating the enzymes involved [i.e., phosphoglycerate dehydrogenase (PGHDH), phosphoserine aminotransferase 1 (PSAT1), phosphoserine phosphatase (PSPH)], leading to serine generation and antioxidant machinery intermediates (cysteine and glutathione). Serine hydroxymethyltransferase (SHMT) mediates the conversion between serine and glycine with the concurrent transformation of tetrahydrofolate (THF) into 5,10-methylenetetrahydrofolate (meTHF). Aldehyde dehydrogenase 1 family member (ALDH1L) mediates the opposite reaction with concurrent generation of NADPH, similarly methylenetetrahydrofolate dehydrogenase (MTHDF) transform meTHF into 10-formyltetrahydrofolate (F-THF) with concurrent generation of nicotinamide adenine dinucleotide phosphate. The main chemotherapy agents are represented in blue. Dehydroepiandrosterone (DHEA), epigallocatechin gallate (EGCG), amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), 6-aminonicotinamide (6-AN), and 5-fluorouracil (5-FU).

Figure 2

Oncogenic deregulation in mitochondrial metabolism. Physiological mitochondrial metabolism is deranged in cancer by several oncogenic signaling (depicted in red). Inhibition of specific mitochondrial enzymes [i.e., succinate dehydrogenase (SDH) and fumarate hydratase (FH)] or specific mutation [i.e., isocitrate dehydrogenase (IDH)] leads to cellular transformation via the generation of oncometabolites. Similarly, oncogenic drivers affect electron transport chain activity and promote increased oxidative stress buffering (e.g., via malic enzyme-ME). Pro-tumorigenic signals are represented in red and anti-tumorigenic in green. Enzymes with a double pro/anti-tumorigenic signal according to the type of tumor (i.e., PGC1 alpha and HIF1α) are represented in orange. The main chemotherapy agents are represented in blue.