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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)798-815.e5
JournalCancer Cell
Volume35
Issue number5
DOIs
Publication statusPublished - May 13 2019

    Fingerprint

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Elgendy, M., Cirò, M., Hosseini, A., Weiszmann, J., Mazzarella, L., Ferrari, E., Cazzoli, R., Curigliano, G., DeCensi, A., Bonanni, B., Budillon, A., Pelicci, P. G., Janssens, V., Ogris, M., Baccarini, M., Lanfrancone, L., Weckwerth, W., Foiani, M., & Minucci, S. (2019). Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis. Cancer Cell, 35(5), 798-815.e5. https://doi.org/10.1016/j.ccell.2019.03.007