Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3ß-MCL-1 Axis.
Cancer Cell
; 35(5): 798-815.e5, 2019 05 13.
Article
em En
| MEDLINE
| ID: mdl-31031016
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 3ß (GSK3ß) activation downstream of PP2A, leading to a decline in the pro-survival protein MCL-1, and cell death. Mechanistically, specific activation of the PP2A-GSK3ß 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 GSK3ß.
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Jejum
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Hipoglicemia
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Metformina
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Neoplasias
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article