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 3 beta (GSK3 beta) activation downstream of PP2A, leading to a decline in the pro-survival protein MCL-1, and cell death. Mechanistically, specific activation of the PP2A-GSK3 beta axis was the sum of metformin-induced inhibition of CIP2A, a PP2A suppressor, and of upregulation of the PP2A regulatory subunit B56 delta by low glucose, leading to an active PP2A-B568 delta complex with high affinity toward GSK3 beta.
Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis / M. Elgendy, M. Ciro, A. Hosseini, J. Weiszmann, L. Mazzarella, E. Ferrari, R. Cazzoli, G. Curigliano, A. Decensi, B. Bonanni, A. Budillon, P.G. Pelicci, V. Janssens, M. Ogris, M. Baccarini, L. Lanfrancone, W. Weckwerth, M. Foiani, S. Minucci. - In: CANCER CELL. - ISSN 1535-6108. - 35:5(2019 May 13), pp. 798-815.e5.
|Titolo:||Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis|
FOIANI, MARCO (Penultimo)
MINUCCI, SAVERIO (Ultimo)
|Parole Chiave:||caloric restriction; fasting; glucose; GSK3ß; hypoglycemia; MCL1; metabolic plasticity; metformin; PP2A; tumor metabolism|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore MED/06 - Oncologia Medica
|Data di pubblicazione:||13-mag-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.ccell.2019.03.007|
|Appare nelle tipologie:||01 - Articolo su periodico|