TY - JOUR
T1 - Metabolic alterations in highly tumorigenic glioblastoma cells
T2 - Preference for hypoxia and high dependency on glycolysis
AU - Zhou, Yunfei
AU - Zhou, Yan
AU - Shingu, Takashi
AU - Feng, Li
AU - Chen, Zhao
AU - Ogasawara, Marcia
AU - Keating, Michael J.
AU - Kondo, Seiji
AU - Huang, Peng
PY - 2011/9/16
Y1 - 2011/9/16
N2 - 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 therapeuticagentsiseffectiveinkillingthetumor-initiatingcells 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.
AB - 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 therapeuticagentsiseffectiveinkillingthetumor-initiatingcells 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.
UR - http://www.scopus.com/inward/record.url?scp=80052722539&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052722539&partnerID=8YFLogxK
U2 - 10.1074/jbc.M111.260935
DO - 10.1074/jbc.M111.260935
M3 - Article
C2 - 21795717
AN - SCOPUS:80052722539
SN - 0021-9258
VL - 286
SP - 32843
EP - 32853
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -