Review of metabolic pathways activated in cancer cells as determined through isotopic labeling and network analysis

Abstract

Cancer metabolism has emerged as an indispensable part of contemporary cancer research. During the past 10 years, the use of stable isotopic tracers and network analysis have unveiled a number of metabolic pathways activated in cancer cells. Here, we review such pathways along with the particular tracers and labeling observations that led to the discovery of their rewiring in cancer cells. The list of such pathways comprises the reductive metabolism of glutamine, altered glycolysis, serine and glycine metabolism, mutant isocitrate dehydrogenase (IDH) induced reprogramming and the onset of acetate metabolism. Additionally, we demonstrate the critical role of isotopic labeling and network analysis in identifying these pathways. The alterations described in this review do not constitute a complete list, and future research using these powerful tools is likely to discover other cancer-related pathways and new metabolic targets for cancer therapy.

Glyceraldehyde 3‐phosphate dehydrogenase modulates nonoxidative pentose phosphate pathway to provide anabolic precursors in hypoxic tumor cells

“…We analyzed 13 C‐labeling of 3‐phosphoglycerate (3PG), PEP and ribose extracted from RNA using GC–MS. The M1/M2 isotopomer ratio of 3PG and PEP provides a measure of the metabolic activity of the oxidative PPP relatively to glycolysis (Figure H). Intriguingly, the oxidative PPP activities under hypoxia decreased significantly 2‐ and 3‐fold in MDA‐MB‐231 and HepG2, respectively (Figure I).…”

Oxidative pentose phosphate pathway and glucose anaplerosis support maintenance of mitochondrial NADPH pool under mitochondrial oxidative stress

“…Next, we used a [U- 13 (Figure 5d). 22,43 At high production rate of mitochondrial H 2 O 2 , we expected the glucose oxidation rate to increase so as to replenish TCA metabolites and support NADPH regeneration. Table S1).…”

“…12,13,20 For instance, oxidative stress in fibroblast cells led to a shift of glycolytic flux toward the oxidative pentose phosphate pathway to regenerate NADPH. [20][21][22][23] In isolated cardiac myocytes under a pathological workload, the direction of mitochondrial nicotinamide transhydrogenase reaction was reversed, lowering the total NADPH pool and increasing the production of mitochondrial ROS. 24 Similarly, the availability of NADPH in mitochondria along with NADPH-producing enzymes such as isocitrate dehydrogenase 2 (IDH2) and nicotinamide nucleotide transhydrogenase (NNT) was shown to control the antioxidant network for clearance of H 2 O 2 .…”

Positional stable isotope tracer analysis reveals carbon routes during ammonia metabolism of Aedes aegypti mosquitoes

“…In this study, the identification of [ 13 C 1 ] uric acid in mosquito whole body at 6, 12, and 24 h after feeding concurs with the presence and quantification of uric acid in malpighian tubules of blood-fed A. aegypti females at 6, 12, and 24 h after feeding (14,15), and, importantly, it provides evidence that the carbon skeleton of glucose contributes to the synthesis of uric acid, a key antioxidant and nitrogen waste product in blood-fed mosquitoes (14,15). Certainly, the detection of [ 13 C]Ser in mosquito whole body is well-correlated with its possible contribution as one of the sources of carbon for de novo purine synthesis via the production of 5, 10-methylene-tetrahydrofolate (21,31,32).…”