Therapeutic Strategy for Targeting Aggressive Malignant Gliomas by Disrupting Their Energy Balance

摘要: Although abnormal metabolic regulation is a critical determinant of cancer cell behavior, it still unclear how an altered balance between ATP production and consumption contributes to malignancy. Here we show that disruption this energy efficiently suppresses aggressive malignant gliomas driven by mammalian target rapamycin complex 1 (mTORC1) hyperactivation. In mouse glioma model, mTORC1 hyperactivation induced conditional Tsc1 deletion increased numbers glioma-initiating cells (GICs) in vitro vivo Metabolic analysis revealed enhanced mitochondrial biogenesis, as evidenced elevations oxygen rate production. Inhibition synthetase was more effective repressing sphere formation Tsc1-deficient than Tsc1-competent cells, indicating crucial function for bioenergetic capacity GIC expansion. To translate observation into the development novel therapeutics targeting gliomas, screened drug libraries small molecule compounds showing greater efficacy inhibiting proliferation/survival compared with controls. We identified several able preferentially inhibit activity, dramatically reducing levels blocking formation. human patient-derived nigericin, which reportedly stem properties, AMPK phosphorylation associated inactivation induction autophagy led marked decrease loss marker expression. Furthermore, characteristics were markedly suppressed nigericin treatment Thus, mTORC1-driven processes, particularly those involved maintaining cell's balance, may be therapeutic strategy patients.