Table 2 CSC phenotypes that depend on glycolysis to maintain cancer stemness and the abnormally increased metabolites or metabolic pathway products as markers of enhanced CSC stemness and chemotherapy resistance.
From: The metabolic flexibility of quiescent CSC: implications for chemotherapy resistance
CSC phenotype | Abnormally increased metabolic intermediates as markers of enhanced CSC stemness and chemotherapy resistance | Impacts of glycolysis on CSC stemness or chemotherapy resistance | Impacts of glycolysis on the quiescence/proliferation states of CSCs | Reference |
|---|---|---|---|---|
Hepatocellular carcinoma | Lactate and glycolytic ability | The HIF1α/USP22 positive feedback loop upon TP53 inactivation strongly correlates with the CSC subpopulation | The HIF1α/USP22 positive feedback loop in promoting glycolysis and stemness on TP53 inactivation, which is known to control the balance between quiescence and proliferation in CSCs | [49] |
Nasopharyngeal carcinoma | ROS and mitochondrial membrane potential | Glycolysis can sustain self-renewal, deter differentiation and enhance the antioxidant system in CSCs | Ungiven | [9] |
Breast cancer | ROS | Co-inhibition of glycolysis and thioredoxin and GSH pathways suppresses tumor growth, tumor-initiating potential. | Metabolic or oxidative stress generated by 2DG, H2O2, or hypoxia promotes the transition of quiescent(ROSlo) M-BCSCs to a proliferative (ROShi) E-state. | [76] |
Glioblastoma multiforme | Lactate | GBM, particularly the stem cell subpopulation, is sensitive to glycolytic inhibition via lactate dehydrogenase-A inhibitors | Dichloroacetate (100 μM), a compound capable of inhibiting glycolysis metabolism, is capable of hindering CSC proliferation (cell cycle arrest in G2/M phase) | [86] |
Glioblastoma | Serine/glycine | Serine/glycine, as intermediates of glycolysis, participates in and promotes the synthesis of purine and thymidine, which are both precursors of RNA and DNA and induce progression of cell division | Hypoxia affects cancer cells in multiple intertwined ways: including a metabolic adaptation with overexpression of all glycolytic pathway enzymes for pyruvate/lactate synthesis and cell growth arrest coexisting with EMT. | [87] |
Pancreatic cancer | ROS | Inhibition of glycolysis using 2-DG significantly enhances the cytotoxicity of gemcitabine and inhibits CSC and EMT phenotypes both in vitro and in vivo | Inhibition of glycolysis forces CSCs into the proliferative state and improves chemoresistance against gemcitabine. | [88] |
Breast and prostate tumors | Glutamine and glutamate | using secreted frizzled-related protein 4 to inhibit glycolysis is sufficient to inhibit CSC survival in vivo. | Inhibition of glycolysis via sFRP4 makes CSCs vulnerable under conditions of variable glucose content. | [89] |
Hepatocellular carcinoma | Mannose 6-phosphate, myo-Inositol-3-phosphate, fructose 6-phosphate, and glucose 6-phosphate | Increased activation of the pentose phosphate pathway diverts glycolytic intermediates to provide precursors for nucleotide synthesis | Ungiven | [90] |
Pancreatic cancer | Lactate | Hepatocyte growth factor/c-MET/YAP/HIF-1α signaling enhances the expression of hexokinase 2 (HK2) and promotes glycolytic metabolism | HGF/c-MET/YAP/HIF-1α signaling enhanced the expression of Hexokinase 2 (HK2) and promoted glycolytic metabolism, which may facilitate CSC relatively quiescent state. | [91] |
Breast cancer | Unknown | 2-DG significantly inhibits the migration and invasion of Hs578Ts(i) and significantly decreases their ability to resist anoikis | Hs578Ts(i)8 showed an increased glycolysis preference and had a significantly increased proportion of cells with relatively quiescent CSC. | [92] |
