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 language | English |
|---|---|
| Pages (from-to) | 798-815.e5 |
| Journal | Cancer Cell |
| Volume | 35 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 13 2019 |
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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
Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis. / Elgendy, Mohamed; Cirò, Marco; Hosseini, Amir; Weiszmann, Jakob; Mazzarella, Luca; Ferrari, Elisa; Cazzoli, Riccardo; Curigliano, Giuseppe; DeCensi, Andrea; Bonanni, Bernardo; Budillon, Alfredo; Pelicci, Pier Giuseppe; Janssens, Veerle; Ogris, Manfred; Baccarini, Manuela; Lanfrancone, Luisa; Weckwerth, Wolfram; Foiani, Marco; Minucci, Saverio.
In: Cancer Cell, Vol. 35, No. 5, 13.05.2019, p. 798-815.e5.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis
AU - Elgendy, Mohamed
AU - Cirò, Marco
AU - Hosseini, Amir
AU - Weiszmann, Jakob
AU - Mazzarella, Luca
AU - Ferrari, Elisa
AU - Cazzoli, Riccardo
AU - Curigliano, Giuseppe
AU - DeCensi, Andrea
AU - Bonanni, Bernardo
AU - Budillon, Alfredo
AU - Pelicci, Pier Giuseppe
AU - Janssens, Veerle
AU - Ogris, Manfred
AU - Baccarini, Manuela
AU - Lanfrancone, Luisa
AU - Weckwerth, Wolfram
AU - Foiani, Marco
AU - Minucci, Saverio
PY - 2019/5/13
Y1 - 2019/5/13
N2 - 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.
AB - 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.
KW - caloric restriction
KW - fasting
KW - glucose
KW - GSK3ß
KW - hypoglycemia
KW - MCL1
KW - metabolic plasticity
KW - metformin
KW - PP2A
KW - tumor metabolism
UR - http://www.scopus.com/inward/record.url?scp=85065108746&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065108746&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2019.03.007
DO - 10.1016/j.ccell.2019.03.007
M3 - Article
VL - 35
SP - 798-815.e5
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 5
ER -