Glioma-Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK
| Autor: | Yoshitaka Narita, Soichiro Shibui, Atsushi Sato, Chifumi Kitanaka, Kaori Suzuki, Masashi Okada, Shizuka Seino, Jun Sunayama, Takamasa Kayama, Eriko Watanabe, Keita Shibuya |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
endocrine system diseases Cell Population Transplantation Heterologous Mice Nude Biology AMP-Activated Protein Kinases Mice Internal medicine Glioma Cancer Stem Cells Cell Line Tumor medicine Animals Humans Protein kinase A education neoplasms education.field_of_study Mice Inbred BALB C Brain Neoplasms Forkhead Box Protein O3 AMPK Cell Differentiation Forkhead Transcription Factors Cell Biology General Medicine medicine.disease Metformin nervous system diseases medicine.anatomical_structure Endocrinology Glucose Blood-Brain Barrier Cancer research FOXO3 Systemic administration Neoplastic Stem Cells Glioblastoma Developmental Biology medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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