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
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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
C2 - 31031016
AN - SCOPUS:85065108746
VL - 35
SP - 798-815.e5
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 5
ER -