title: Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK.
abstract: 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.
authors.affiliation: Department of Molecular Cancer Science, Yamagata University, Yamagata, Japan. asato@med.id.yamagata-u.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Jun
authors.initials: J
authors.lastname: Sunayama
authors.forename: Masashi
authors.initials: M
authors.lastname: Okada
authors.forename: Eriko
authors.initials: E
authors.lastname: Watanabe
authors.forename: Shizuka
authors.initials: S
authors.lastname: Seino
authors.forename: Keita
authors.initials: K
authors.lastname: Shibuya
authors.forename: Kaori
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Narita
authors.forename: Soichiro
authors.initials: S
authors.lastname: Shibui
authors.forename: Takamasa
authors.initials: T
authors.lastname: Kayama
authors.forename: Chifumi
authors.initials: C
authors.lastname: Kitanaka
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D005947:Glucose; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D005947:Glucose