Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis.
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
Metformin
/ administration & dosage
Mice
Myeloid Cell Leukemia Sequence 1 Protein
/ metabolism
Neoplasms
/ metabolism
Oxidative Phosphorylation
/ drug effects
Protein Phosphatase 2
/ metabolism
Signal Transduction
/ drug effects
Xenograft Model Antitumor Assays
GSK3ß
MCL1
PP2A
caloric restriction
fasting
glucose
hypoglycemia
metabolic plasticity
metformin
tumor metabolism
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
13 05 2019
13 05 2019
Historique:
received:
02
01
2018
revised:
05
01
2019
accepted:
27
03
2019
pubmed:
30
4
2019
medline:
14
2
2020
entrez:
30
4
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31031016
pii: S1535-6108(19)30152-7
doi: 10.1016/j.ccell.2019.03.007
pii:
doi:
Substances chimiques
MCL1 protein, human
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Metformin
9100L32L2N
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Protein Phosphatase 2
EC 3.1.3.16
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
798-815.e5Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.