期刊
STEM CELLS TRANSLATIONAL MEDICINE
卷 1, 期 11, 页码 811-824出版社
ALPHAMED PRESS
DOI: 10.5966/sctm.2012-0058
关键词
Cancer; Cell biology; Cell signaling; Glioma
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Global COE Program of the Japan Society for the Promotion of Science
- National Cancer Center Research and Development Fund [23-A-20]
- Japan Brain Foundation
- Grants-in-Aid for Scientific Research [23791585, 24650644, 24390338] Funding Source: KAKEN
Control of the cancer stem/initiating cell population is considered key to realizing the long-term survival of glioblastoma patients. Recently, we demonstrated that FOXO3 activation is sufficient to induce differentiation of glioma-initiating cells having stem-like properties and inhibit their tumor-initiating potential. Here we identified metformin, an antidiabetic agent, as a therapeutic activator of FOXO3. Metformin activated FOXO3 and promoted differentiation of such stem-like glioma-initiating cells into nontumorigenic cells. Furthermore, metformin promoted FOXO3 activation and differentiation via AMP-activated protein kinase (AMPK) activation, which was sensitive to extracellular glucose availability. Importantly, transient, systemic administration of metformin depleted the self-renewing and tumor-initiating cell population within established tumors, inhibited tumor formation by stem-like glioma-initiating cells in the brain, and provided a substantial survival benefit. Our findings demonstrate that targeting glioma-initiating cells via the AMPK-FOXO3 axis is a viable therapeutic strategy against glioblastoma, with metformin being the most clinically relevant drug ever reported for targeting of glioma-initiating cells. Our results also establish a novel, direct link between glucose metabolism and cancer stem/initiating cells. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:811-824
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