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

Author(s)
Mohamed Elgendy, Marco Cirò, Amir Hosseini, Jakob Weiszmann, Luca Mazzarella, Elisa Ferrari, Riccardo Cazzoli, Giuseppe Curigliano, Andrea DeCensi, Bernardo Bonanni, Alfredo Budillon, Pier Giuseppe Pelicci, Veerle Janssens, Manfred Ogris, Manuela Baccarini, Luisa Lanfrancone, Wolfram Weckwerth, Marco Foiani, Saverio Minucci
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.

Organisation(s)
Research Platform Vienna Metabolomics Center, Department of Ecogenomics and Systems Biology, Department of Pharmaceutical Chemistry, Department of Microbiology, Immunobiology and Genetics, Large-Instrument Facility for Mass Spectrometry in Life Sciences
Journal
Cancer Cell
Volume
35
Pages
798-815.e5
ISSN
1535-6108
DOI
https://doi.org/10.1016/j.ccell.2019.03.007
Publication date
2019
Publication status
Published
Peer reviewed
Yes
Austrian Fields of Science 2012
301206 Pharmacology
Portal url
https://ucris.univie.ac.at/portal/en/publications/combination-of-hypoglycemia-and-metformin-impairs-tumor-metabolic-plasticity-and-growth-by-modulating-the-pp2agsk3mcl1-axis(fdcd3686-5fe2-4e82-8618-a2643bb78a76).html