Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis
| Autor: | Amir Hosseini, Manuela Baccarini, Wolfram Weckwerth, Alfredo Budillon, Mohamed Elgendy, Pier Giuseppe Pelicci, Giuseppe Curigliano, Manfred Ogris, Andrea Decensi, Marco Ciro, Riccardo Cazzoli, Elisa Ferrari, Luca Mazzarella, Luisa Lanfrancone, Jakob Weiszmann, Veerle Janssens, Marco Foiani, Bernardo Bonanni, Saverio Minucci |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research endocrine system diseases Oxidative Phosphorylation ACTIVATION Mice 0302 clinical medicine GSK-3 Neoplasms Intermittent fasting Glycolysis Protein Phosphatase 2 Chemistry Fasting Metformin PP2A APOPTOSIS Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Life Sciences & Biomedicine RESTRICTION medicine.drug Signal Transduction medicine.medical_specialty Cell Survival BREAST-CANCER PROLIFERATION Oxidative phosphorylation Hypoglycemia 03 medical and health sciences Downregulation and upregulation SUPPRESSOR Internal medicine Cell Line Tumor KINASE TUMORIGENESIS medicine Animals Humans GSK3B Cell Proliferation Science & Technology Glycogen Synthase Kinase 3 beta nutritional and metabolic diseases Cell Biology DEGRADATION medicine.disease HCT116 Cells Xenograft Model Antitumor Assays 030104 developmental biology Endocrinology Myeloid Cell Leukemia Sequence 1 Protein RESISTANCE HeLa Cells |
| Zdroj: | Cancer cell. 35(5) |
| ISSN: | 1878-3686 |
| Popis: | Tumor cells may adapt to metabolic challenges by alternating between glycolysis and oxidative phosphorylation (OXPHOS). To target this metabolic plasticity, we combined intermittent fasting, a clinically feasible approach to reduce glucose availability, with the OXPHOS inhibitor metformin. In mice exposed to 24-h feeding/fasting cycles, metformin impaired tumor growth only when administered during fasting-induced hypoglycemia. Synergistic anti-neoplastic effects of the metformin/hypoglycemia combination were mediated by glycogen synthase kinase 3β (GSK3β) activation downstream of PP2A, leading to a decline in the pro-survival protein MCL-1, and cell death. Mechanistically, specific activation of the PP2A-GSK3β axis was the sum of metformin-induced inhibition of CIP2A, a PP2A suppressor, and of upregulation of the PP2A regulatory subunit B56δ by low glucose, leading to an active PP2A-B56δ complex with high affinity toward GSK3β. ispartof: CANCER CELL vol:35 issue:5 pages:798-+ ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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