Recent studies suggest that a small subpopulation of malignant cells with stem-like properties is resistant to
chemotherapy and may be responsible for the existence of
residual cancer after treatment. We have isolated highly tumorigenic
cancer cells with 100-fold increase in
tumor initiating capacity from the
tumor xenografts of human
glioblastoma U87 cells in mice. These cells exhibit stem-like properties and show unique energy metabolic characteristics including low mitochondrial respiration, increased glycolysis for
ATP generation, and preference for
hypoxia to maintain their stemness and
tumor forming capacity. Mechanistically, mitochondrial depression in the highly tumorigenic cells occurs mainly at complex II of the electron transport chain with a down-regulation of the
succinate dehydrogenase subunit B, leading to deregulation of
hypoxia-inducible factors. Under
hypoxia, the stem-like
cancer cells are resistant to conventional
anticancer agents but are sensitive to glycolytic inhibition. Furthermore, combination of glycolytic inhibition with standard therapeutic agents is effective in killing the tumor-initiating cells in vitro and inhibits
tumor formation in vivo. Our study suggests that stem-like
cancer cells prefer a low
oxygen microenvironment and actively utilize the glycolytic pathway for
ATP generation. Inhibition of glycolysis may be an effective strategy to eradicate
residual cancer stem cells that are otherwise resistant to chemotherapeutic agents in their hypoxic niches.