Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis

Mohamed Elgendy; Marco Cirò; Amir Hosseini; Jakob Weiszmann; Luca Mazzarella; Elisa Ferrari; Riccardo Cazzoli; Giuseppe Curigliano; Andrea DeCensi; Bernardo Bonanni; Alfredo Budillon; Pier Giuseppe Pelicci; Veerle Janssens; Manfred Ogris; Manuela Baccarini; Luisa Lanfrancone; Wolfram Weckwerth; Marco Foiani; Saverio Minucci

doi:10.1016/j.ccell.2019.03.007

Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis

Mohamed Elgendy, Marco Cirò, Amir Hosseini, Jakob Weiszmann, Luca Mazzarella, Elisa Ferrari, Riccardo Cazzoli, Giuseppe Curigliano, Andrea DeCensi, Bernardo Bonanni, Alfredo Budillon, Pier Giuseppe Pelicci, Veerle Janssens, Manfred Ogris, Manuela Baccarini, Luisa Lanfrancone, Wolfram Weckwerth, Marco Foiani, Saverio Minucci

Istituto Nazionale Tumori Fondazione G. Pascale

Research output: Contribution to journal › Article › peer-review

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	https://doi.org/10.1016/j.ccell.2019.03.007
Publication status	Published - May 13 2019

Keywords

caloric restriction
fasting
glucose
GSK3ß
hypoglycemia
MCL1
metabolic plasticity
metformin
PP2A
tumor metabolism

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

Access to Document

10.1016/j.ccell.2019.03.007

Fingerprint Dive into the research topics of 'Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis'. Together they form a unique fingerprint.

Cite this

Elgendy, M., Cirò, M., Hosseini, A., Weiszmann, J., Mazzarella, L., Ferrari, E., Cazzoli, R., Curigliano, G., DeCensi, A., Bonanni, B., Budillon, A., Pelicci, P. G., Janssens, V., Ogris, M., Baccarini, M., Lanfrancone, L., Weckwerth, W., Foiani, M., & Minucci, S. (2019). Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis. Cancer Cell, 35(5), 798-815.e5. https://doi.org/10.1016/j.ccell.2019.03.007

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 › peer-review

Elgendy, M, Cirò, M, Hosseini, A, Weiszmann, J, Mazzarella, L, Ferrari, E, Cazzoli, R, Curigliano, G, DeCensi, A, Bonanni, B, Budillon, A, Pelicci, PG, Janssens, V, Ogris, M, Baccarini, M, Lanfrancone, L, Weckwerth, W, Foiani, M & Minucci, S 2019, 'Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis', Cancer Cell, vol. 35, no. 5, pp. 798-815.e5. https://doi.org/10.1016/j.ccell.2019.03.007

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. / Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis. In: Cancer Cell. 2019 ; Vol. 35, No. 5. pp. 798-815.e5.

@article{8b25e1ddd0084621a1a065d2f6f2ea21,

title = "Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis",

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.",

keywords = "caloric restriction, fasting, glucose, GSK3{\ss}, hypoglycemia, MCL1, metabolic plasticity, metformin, PP2A, tumor metabolism",

author = "Mohamed Elgendy and Marco Cir{\`o} and Amir Hosseini and Jakob Weiszmann and Luca Mazzarella and Elisa Ferrari and Riccardo Cazzoli and Giuseppe Curigliano and Andrea DeCensi and Bernardo Bonanni and Alfredo Budillon and Pelicci, {Pier Giuseppe} and Veerle Janssens and Manfred Ogris and Manuela Baccarini and Luisa Lanfrancone and Wolfram Weckwerth and Marco Foiani and Saverio Minucci",

year = "2019",

month = may,

day = "13",

doi = "10.1016/j.ccell.2019.03.007",

language = "English",

volume = "35",

pages = "798--815.e5",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

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

C2 - 31031016

AN - SCOPUS:85065108746

VL - 35

SP - 798-815.e5

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 5

ER -