Figure 6. Enzyme-associated metabolic adaptation.

Enzyme-mediated metabolic adaptation is a dynamic process, resulting from crosstalk(s) between cellular signaling, metabolic pathways, and microenvironment. A. CSCs in serum-free culture. Growth factors, high glucose level and insulin in artificial culture media activate multiple signaling pathways, inducing expression of stemness-related factors and augmenting glycolytic metabolism. Thus, clonal spheres cultured from serum-free system are not ideal model to represent the metabolic profile of CSCs. B. CSCs under physiological hypoxia. HIF1α is a transcriptional factor activating the expression of many glycolytic enzymes including PGK1, PKM and LDH-A. High level of HIF induced by hypoxia, together with the high expression of GLUT and detoxifying enzymes, mediates the metabolic adaptation under the physiological condition. C. CSCs under stresses. CSCs can modulate dominant metabolic pathways to adapt different environmental stresses. When encountering chemotherapy, CSCs can increase the PPP flux to produce more NADPH, which is involved in eliminating hazardous substances such as ROS, as well as regenerating reductive GSH. Under starvation, CSCs can use ketone bodies to satisfy their energetic demand and induce epigenetic modification to survive.