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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Fasting / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Glycolysis / drug effects
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Hypoglycemia / etiology
  • Hypoglycemia / metabolism*
  • Metformin / administration & dosage*
  • Metformin / pharmacology
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Neoplasms / metabolism
  • Neoplasms / therapy*
  • Oxidative Phosphorylation / drug effects
  • Protein Phosphatase 2 / metabolism
  • Signal Transduction / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Metformin
  • Glycogen Synthase Kinase 3 beta
  • Protein Phosphatase 2