Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression

Abstract

Metabolic reprogramming is widely observed during cancer development to confer cancer cells the ability to survive and proliferate, even under the stressed, such as nutrient-limiting, conditions. It is famously known that cancer cells favor the "Warburg effect", i.e., the enhanced glycolysis or aerobic glycolysis, even when the ambient oxygen supply is sufficient. In addition, deregulated anabolism/catabolism of fatty acids and amino acids, especially glutamine, serine and glycine, have been identified to function as metabolic regulators in supporting cancer cell growth. Furthermore, extensive crosstalks are being revealed between the deregulated metabolic network and cancer cell signaling. These exciting advancements have inspired new strategies for treating various malignancies by targeting cancer metabolism. Here we review recent findings related to the regulation of glucose, fatty acid and amino acid metabolism, their crosstalk, and relevant cancer therapy strategy.

Keywords: Amino acid; Cancer; Fatty acid; Glucose; Metabolism.

Fig. 1

Regulation of glucose metabolism in cancer cells. Glucose metabolism contains glycolysis, pentose phosphate pathway (PPP), serine synthesis pathway (SSP) in the cytoplasm and TCA cycle in the mitochondrion. These pathways are generally altered in tumor cells. Please see more detail in the text. GLUT glucose transporter, G6P glucose-6-phosphate, F6P fructose-6-phosphate, F1,6P fructose-1,6-bisphosphate, GA3P glyceraldehyde 3-phosphate, 1,3-DPG 1,3-disphosphoglycerate, 3PG 3-phospho-glycerate, 2PG 2-phospho-glycerate, PEP phosphoenolpyruvate, R5P ribose-5-phosphate, HK hexokinase, PFK phosphofructokinase, ALDOA aldolase A, fructose-bisphosphate, GAPDH glyceraldehyde-3-phosphate dehydrogenase, PGK1 phosphoglycerate kinase 1, PGAM1 phosphoglycerate mutase 1, ENO1 alpha-enolase, PKM2 pyruvate kinase isozyme type 2, LDHA lactate dehydrogenase A, PDK1 pyruvate dehydrogenase kinase 1, PDH pyruvate dehydrogenase, G6PD glucose-6-phosphate dehydrogenase, 6PGL 6-phosphogluconolactone, 6PGD 6-phosphogluconate dehydrogenase, TKT transketolase, PHGDH phosphoglycerate dehydrogenase, PSAT1 phosphoserine aminotransferase 1, PSPH phosphoserine phosphatase, SHMT serine hydroxymethyltransferase, TCA cycle tricarboxylic acid cycle

Fig. 2

Fatty acid anabolism and catabolism in cancer cells. Both fatty acid anabolism and catabolism are dysregulated in cancer cells. Please see more detail in the text. FA fatty acid, CIC citrate carrier, CPT1 carnitine palmitoyl transferase 1, ACLY ATP citrate lyase, ACC acetyl-CoA carboxylase, MCD malonyl-CoA decarboxylase, FASN fatty acid synthase, ACS acetyl-CoA synthetase

Fig. 3

Amino acid metabolism in cancer cells and its crosstalk with other metabolism pathways. Amino acids synthesis, utilization, and involvement in other metabolism pathways are usually changed in cancer cells. Please see more detail in the text. α-KG α-ketoglutarate, GSA glutamic semialdehyde, P5C pyrroline-5-carboxylate, GLS glutaminase, GLUD1 glutamate dehydrogenase 1, ASS argininosuccinate synthetase, ASL argininosuccinate lyase, ADI arginine deiminase, IDH1 isocitrate dehydrogenase-1, ACO1 aconitase 1, SSR serine racemase. Dashed arrows represent indirect effects or serial reactions