Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy

Table 1 Summary of the role and mechanism of amino acid metabolism in cancer stem cells

Amino acid metabolism	Possible mechanisms in CSCs	Role in CSC properties
Methionine metabolism	Direct nutrients; Genetic modification; DNA biosynthesis	Self-renewal; tumorigenicity
Tryptophan metabolism	Immune escape and resistance; regulates stem genes and signal pathway	Self-renewal; survival
Threonine metabolism	Upregulated in colon CSCs (HCT116), but mechanism is unknown	Self-renewal
Lysine metabolism	Reduces ROS and activates Wnt pathway	Self-renewal
Leucine metabolism	Regulates CD13+ CSCs survival in hepatocellular carcinoma, but mechanism is unknown; Inhibits stemness and growth of EpCAM+ hepatocellular carcinoma stem cells by activating MTORC1	Stemness; survival
Valine metabolism	Regulates CD13+ CSCs survival in hepatocellular carcinoma, but mechanism is unknown	survival
Phenylalanine metabolism	Unknown	Unknown
Isoleucine metabolism	Inhibits stemness and growth of EpCAM+ hepatocellular carcinoma stem cells by activating MTORC1	Stemness
Histidine metabolism	Unknown	Unknown
Glycine metabolism	Direct nutrients within a certain range; epigenetic modification; DNA synthesis; regulates redox homeostasis; carries out TCA cycle	Self-renewal; survival; tumorigenicity; metastasis
Serine metabolism	Regulates redox homeostasis; shunts glucose metabolism; carries out TCA cycle; influences T cell proliferation	Self-renewal; survival; tumorigenicity; stemness; metastasis; resistance
Glutamine metabolism	Direct nutrients; carries out TCA cycle; synthesis of nucleic acids; maintains redox balance; regulates tumor immunity	Self-renewal; survival; tumorigenicity; stemness; resistance
Glutamate metabolism	Carries out TCA cycle; participates serine metabolism; maintains redox balance	Self-renewal; survival; tumorigenicity; stemness
Cysteine metabolism	Mainly maintains redox balance	Self-renewal; survival; tumorigenicity; resistance; metastasis
Aspartate metabolism	Replenishes TCA cycle; synthesis of nucleic acids	Survival
Asparagine metabolism	Replenishes TCA cycle; synthesis of nucleic acids; exchanges amino acids	Survival
Alanine metabolism	Upregulated in breast CSCs, but mechanism is unknown; regulates T cell function	Self-renewal;stemness; tumorigenicity
Arginine metabolism	Participates in cell proliferation and urea cycle; regulates tumor immunity	Self-renewal
Proline metabolism	Maybe epigenetic modification and transform steadily; synthesize collagen	Self-renewal; stemness; metastasis
Tyrosine metabolism	Provides energy; Foxd3 acetylation	Self-renewal

CSC: Cancer stem cell; TCA cycle: Tricarboxylic acid cycle.

Table 2 Potential enzymes targets for cancer stem cell therapy, role in metabolism, treatment strategy in cancer stem cell-based therapy

Enzyme	Role in amino acid metabolism	CSC therapy
MTase	Translates homocysteine to methionine	Inhibition
MATα2	Induces the production of SAM	Inhibition
IDO1	Catalyzes tryptophan into kynurenine	Inhibition
TDO2	Catalyzes tryptophan into kynurenine	Inhibition
GLDC	Catalyzes glycine into NH3, CO2 and CH2-THF	Inhibition (except gastric cancer, better inhibit SHMT and GCAT simultaneously)
PHGDH	Catalyzes 3P-glycerate into 3-P-OH-pyruvate	Inhibition
SHMT1/2	Completes the conversion between serine and glycine	Inhibition
GLS1	Catalyzes glutamine into glutamate	Inhibition
GDH	Catalyzes glutamate into α-KG	Inhibition
CBS	Translates homocysteine to cystathionine	Inhibition
CGL	Catalyzes cystathionine to cysteine	Inhibition
GCL	Catalyzes the production of γ-glutamyl-cysteine	Inhibition
GSS	Catalyzes GSH production	Inhibition
GOT1	Catalyzes the production of oxaloacetate from aspartate	Inhibition
GPT2	Catalyzes transamination between alanine and α-KG to pyruvate and glutamate	Inhibition
PRODH	Oxidize proline to glutamate	Inhibition

CSC: Cancer stem cell; MTase: Methyltransferase; MAT: Methionine adenosyltransferase; SAM: S-adenosine methionine; IDO1: Indoleamine-2,3-dioxygenase-1; TDO2: Tryptophan 2,3-dioxygenase; GLDC: Glycine decarboxylase; 1C-THF: One-canton tetrahydrofolate; PHGDH: Phosphoglycerate dehydrogenase; SHMT: Serine hydroxymethyl transferase; GCAT: Glycine C-acetyltransferase; GLS: Glutaminase; GDH: Glutamate dehydrogenase; α-KG: α-ketoglutarate; CBS: Cystathionine β synthase; CGL: Cystathionine γ lyase; GCL: Glutamate cysteine ligase; GSS: Glutathione synthetase; GSH: Glutathione; GOT: Aspartate aminotransferase; GPT2: Glutamic pyruvate transaminase; PRODH: Proline dehydrogenase.