Cancer Cell
Volume 35, Issue 5, 13 May 2019, Pages 798-815.e5
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Article
Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis

https://doi.org/10.1016/j.ccell.2019.03.007Get rights and content
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Highlights

  • Metformin plus fasting-induced hypoglycemia synergistically reduces tumor growth

  • PP2A-GSK3β-MCL-1 axis mediates the synergistic cytotoxicity of the combination

  • Simultaneous CIP2A inhibition and B56δ upregulation dictate combination specificity

Summary

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

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

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Present address: Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria

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