Therapeutic strategy for targeting aggressive malignant gliomas by disrupting their energy balance

Ahmed M. Hegazy, Daisuke Yamada, Masahiko Kobayashi, Susumu Kohno, Masaya Ueno, Mohamed A.E. Ali, Kumiko Ohta, Yuko Tadokoro, Yasushi Ino, Tomoki Todo, Tomoyoshi Soga, Chiaki Takahashi, Atsushi Hirao

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)21496-21509
Number of pages14
JournalJournal of Biological Chemistry
Volume291
Issue number41
DOIs
Publication statusPublished - Oct 7 2016
Externally publishedYes

Fingerprint

Energy balance
Glioma
Adenosine Triphosphate
Nigericin
Cells
Therapeutics
Phosphorylation
AMP-Activated Protein Kinases
Ligases
Stem cells
mechanistic target of rapamycin complex 1
Oxygen
Molecules
Small Molecule Libraries
Neoplasms
Neoplastic Stem Cells
Pharmaceutical Preparations
Autophagy
Organelle Biogenesis
Oxygen Consumption

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Therapeutic strategy for targeting aggressive malignant gliomas by disrupting their energy balance. / Hegazy, Ahmed M.; Yamada, Daisuke; Kobayashi, Masahiko; Kohno, Susumu; Ueno, Masaya; Ali, Mohamed A.E.; Ohta, Kumiko; Tadokoro, Yuko; Ino, Yasushi; Todo, Tomoki; Soga, Tomoyoshi; Takahashi, Chiaki; Hirao, Atsushi.

In: Journal of Biological Chemistry, Vol. 291, No. 41, 07.10.2016, p. 21496-21509.

Research output: Contribution to journalArticle

Hegazy, AM, Yamada, D, Kobayashi, M, Kohno, S, Ueno, M, Ali, MAE, Ohta, K, Tadokoro, Y, Ino, Y, Todo, T, Soga, T, Takahashi, C & Hirao, A 2016, 'Therapeutic strategy for targeting aggressive malignant gliomas by disrupting their energy balance', Journal of Biological Chemistry, vol. 291, no. 41, pp. 21496-21509. https://doi.org/10.1074/jbc.M116.734756
Hegazy, Ahmed M. ; Yamada, Daisuke ; Kobayashi, Masahiko ; Kohno, Susumu ; Ueno, Masaya ; Ali, Mohamed A.E. ; Ohta, Kumiko ; Tadokoro, Yuko ; Ino, Yasushi ; Todo, Tomoki ; Soga, Tomoyoshi ; Takahashi, Chiaki ; Hirao, Atsushi. / Therapeutic strategy for targeting aggressive malignant gliomas by disrupting their energy balance. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 41. pp. 21496-21509.
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