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Cancer Cell. 2019 May 13;35(5):798-815.e5. doi: 10.1016/j.ccell.2019.03.007. Epub 2019 Apr 25.

Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis.

Author information

1
Department of Experimental Oncology, European Institute of Oncology, IEO, via Adamello 16, 20139 Milan, Italy. Electronic address: mohamed.elgendy@univie.ac.at.
2
Experimental Therapeutics Program, IFOM - The FIRC Institute for Molecular Oncology Foundation, Via Adamello 16, 20139 Milan, Italy.
3
Department of Experimental Oncology, European Institute of Oncology, IEO, via Adamello 16, 20139 Milan, Italy.
4
Department of Ecogenomics and Systems Biology, Faculty of Sciences, University of Vienna, Vienna, Austria; Vienna Metabolomics Center (VIME), University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
5
Division of Early Drug Development, European Institute of Oncology (IEO), IRCCS, Milan, Italy.
6
Medical Oncology Unit, Ospedali Galliera, 16128 Genova, Italy.
7
Division of Chemoprevention, European Institute of Oncology (IEO), Milan, Italy.
8
Experimental Pharmacology Unit, Laboratori di Mercogliano, Istituto Nazionale Tumori, IRCCS-Fondazione G. Pascale, Napoli, Italy.
9
Department of Experimental Oncology, European Institute of Oncology, IEO, via Adamello 16, 20139 Milan, Italy; Department of Oncology and Hemato-Oncology, Università Degli Studi di Milano, Milan, Italy.
10
Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
11
Laboratory of MacroMolecular Cancer Therapeutics (MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
12
Department of Microbiology, Immunobiology and Genetics, Center for Molecular Biology of the University of Vienna, Max F. Perutz Laboratories, Vienna Biocenter (VBC), 1030 Vienna, Austria.
13
Experimental Therapeutics Program, IFOM - The FIRC Institute for Molecular Oncology Foundation, Via Adamello 16, 20139 Milan, Italy; Department of Oncology and Hemato-Oncology, Università Degli Studi di Milano, Milan, Italy.
14
Department of Experimental Oncology, European Institute of Oncology, IEO, via Adamello 16, 20139 Milan, Italy; Department of Biosciences, University of Milan, 20100 Milan, Italy. Electronic address: saverio.minucci@ieo.it.

Abstract

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.

KEYWORDS:

GSK3ß; MCL1; PP2A; caloric restriction; fasting; glucose; hypoglycemia; metabolic plasticity; metformin; tumor metabolism

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