title: Therapeutic Strategy for Targeting Aggressive Malignant Gliomas by Disrupting Their Energy Balance.
abstract: Although abnormal metabolic regulation is a critical determinant of cancer cell behavior, it is still unclear how an altered balance between ATP production and consumption contributes to malignancy. Here we show that disruption of this energy balance efficiently suppresses aggressive malignant gliomas driven by mammalian target of rapamycin complex 1 (mTORC1) hyperactivation. In a mouse glioma model, mTORC1 hyperactivation induced by conditional Tsc1 deletion increased numbers of glioma-initiating cells (GICs) in vitro and in vivo Metabolic analysis revealed that mTORC1 hyperactivation enhanced mitochondrial biogenesis, as evidenced by elevations in oxygen consumption rate and ATP production. Inhibition of mitochondrial ATP synthetase was more effective in repressing sphere formation by Tsc1-deficient glioma cells than that by Tsc1-competent glioma cells, indicating a crucial function for mitochondrial bioenergetic capacity in GIC expansion. To translate this observation into the development of novel therapeutics targeting malignant gliomas, we screened drug libraries for small molecule compounds showing greater efficacy in inhibiting the proliferation/survival of Tsc1-deficient cells compared with controls. We identified several compounds able to preferentially inhibit mitochondrial activity, dramatically reducing ATP levels and blocking glioma sphere formation. In human patient-derived glioma cells, nigericin, which reportedly suppresses cancer stem cell properties, induced AMPK phosphorylation that was associated with mTORC1 inactivation and induction of autophagy and led to a marked decrease in sphere formation with loss of GIC marker expression. Furthermore, malignant characteristics of human glioma cells were markedly suppressed by nigericin treatment in vivo Thus, targeting mTORC1-driven processes, particularly those involved in maintaining a cancer cell's energy balance, may be an effective therapeutic strategy for glioma patients.
authors: From the Division of Molecular Genetics.
authors: Ahmed M
authors: AM
authors: Hegazy
authors: From the Division of Molecular Genetics.
authors: Daisuke
authors: D
authors: Yamada
authors: From the Division of Molecular Genetics.
authors: Masahiko
authors: M
authors: Kobayashi
authors: Division of Oncology and Molecular Biology, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934.
authors: Susumu
authors: S
authors: Kohno
authors: From the Division of Molecular Genetics.
authors: Masaya
authors: M
authors: Ueno
authors: From the Division of Molecular Genetics.
authors: Mohamed A E
authors: MA
authors: Ali
authors: From the Division of Molecular Genetics.
authors: Kumiko
authors: K
authors: Ohta
authors: From the Division of Molecular Genetics.
authors: Yuko
authors: Y
authors: Tadokoro
authors: the Laboratory of Innovative Cancer Therapy, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, and.
authors: Yasushi
authors: Y
authors: Ino
authors: the Laboratory of Innovative Cancer Therapy, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, and.
authors: Tomoki
authors: T
authors: Todo
authors: the Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan.
authors: Tomoyoshi
authors: T
authors: Soga
authors: Division of Oncology and Molecular Biology, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934.
authors: Chiaki
authors: C
authors: Takahashi
authors: From the Division of Molecular Genetics, ahirao@staff.kanazawa-u.ac.jp.
authors: Atsushi
authors: A
authors: Hirao
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000255:Adenosine Triphosphate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D025261:Mitochondrial Proton-Translocating ATPases
keywords: ATP; brain tumor; drug screening; mammalian target of rapamycin (mTOR); mitochondria