Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module

Laura Di Magno; Simona Manni; Fiorella Di Pastena; Sonia Coni; Alberto Macone; Sara Cairoli; Manolo Sambucci; Paola Infante; Marta Moretti; Marialaura Petroni; Carmine Nicoletti; Carlo Capalbo; Enrico De Smaele; Lucia Di Marcotullio; Giuseppe Giannini; Luca Battistini; Bianca Maria Goffredo; Egidio Iorio; Enzo Agostinelli; Marella Maroder; Gianluca Canettieri

doi:10.1016/j.celrep.2020.01.024

Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module

Laura Di Magno, Simona Manni, Fiorella Di Pastena, Sonia Coni, Alberto Macone, Sara Cairoli, Manolo Sambucci, Paola Infante, Marta Moretti, Marialaura Petroni, Carmine Nicoletti, Carlo Capalbo, Enrico De Smaele, Lucia Di Marcotullio, Giuseppe Giannini, Luca Battistini, Bianca Maria Goffredo, Egidio Iorio, Enzo Agostinelli, Marella MaroderGianluca Canettieri

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

Abstract

The antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as model, we show here that at clinically relevant concentrations, phenformin elicits a significant therapeutic effect through a redox-dependent but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Because ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy.

Original language	English
Pages (from-to)	1735-1752.e7
Journal	Cell Reports
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2020.01.024
Publication status	Published - Feb 11 2020

Keywords

biguanides
cancer
complex I
CtBP2
Hedgehog
metformin
mGPD
NADH
phenformin
redox

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Di Magno, L., Manni, S., Di Pastena, F., Coni, S., Macone, A., Cairoli, S., Sambucci, M., Infante, P., Moretti, M., Petroni, M., Nicoletti, C., Capalbo, C., De Smaele, E., Di Marcotullio, L., Giannini, G., Battistini, L., Goffredo, B. M., Iorio, E., Agostinelli, E., ... Canettieri, G. (2020). Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module. Cell Reports, 30(6), 1735-1752.e7. https://doi.org/10.1016/j.celrep.2020.01.024

Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module. / Di Magno, Laura; Manni, Simona; Di Pastena, Fiorella; Coni, Sonia; Macone, Alberto; Cairoli, Sara ; Sambucci, Manolo; Infante, Paola; Moretti, Marta; Petroni, Marialaura; Nicoletti, Carmine; Capalbo, Carlo; De Smaele, Enrico; Di Marcotullio, Lucia; Giannini, Giuseppe; Battistini, Luca ; Goffredo, Bianca Maria ; Iorio, Egidio; Agostinelli, Enzo; Maroder, Marella; Canettieri, Gianluca.

In: Cell Reports, Vol. 30, No. 6, 11.02.2020, p. 1735-1752.e7.

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

Di Magno, L, Manni, S, Di Pastena, F, Coni, S, Macone, A, Cairoli, S , Sambucci, M, Infante, P, Moretti, M, Petroni, M, Nicoletti, C, Capalbo, C, De Smaele, E, Di Marcotullio, L, Giannini, G, Battistini, L , Goffredo, BM , Iorio, E, Agostinelli, E, Maroder, M & Canettieri, G 2020, 'Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module', Cell Reports, vol. 30, no. 6, pp. 1735-1752.e7. https://doi.org/10.1016/j.celrep.2020.01.024

Di Magno, Laura ; Manni, Simona ; Di Pastena, Fiorella ; Coni, Sonia ; Macone, Alberto ; Cairoli, Sara ; Sambucci, Manolo ; Infante, Paola ; Moretti, Marta ; Petroni, Marialaura ; Nicoletti, Carmine ; Capalbo, Carlo ; De Smaele, Enrico ; Di Marcotullio, Lucia ; Giannini, Giuseppe ; Battistini, Luca ; Goffredo, Bianca Maria ; Iorio, Egidio ; Agostinelli, Enzo ; Maroder, Marella ; Canettieri, Gianluca. / Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module. In: Cell Reports. 2020 ; Vol. 30, No. 6. pp. 1735-1752.e7.

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title = "Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module",

abstract = "The antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as model, we show here that at clinically relevant concentrations, phenformin elicits a significant therapeutic effect through a redox-dependent but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Because ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy.",

keywords = "biguanides, cancer, complex I, CtBP2, Hedgehog, metformin, mGPD, NADH, phenformin, redox",

author = "{Di Magno}, Laura and Simona Manni and {Di Pastena}, Fiorella and Sonia Coni and Alberto Macone and Sara Cairoli and Manolo Sambucci and Paola Infante and Marta Moretti and Marialaura Petroni and Carmine Nicoletti and Carlo Capalbo and {De Smaele}, Enrico and {Di Marcotullio}, Lucia and Giuseppe Giannini and Luca Battistini and Goffredo, {Bianca Maria} and Egidio Iorio and Enzo Agostinelli and Marella Maroder and Gianluca Canettieri",

note = "Funding Information: We thank Ulupi Jhala and Rob Screaton for critical reading of the manuscript, editing, and discussion; Dr. Robert Wechsler-Reya for Math1-CRE;Ptch1 loxP/loxP mice; and Dr. Yoon-Jae Cho for Med1-MB cells. This work was supported by AIRC (grants IG 17575 and IG 20801 ); Istituto Pasteur, Fondazione Cenci-Bolognetti ; Fondazione Enrico ed Enrica Sovena ; Istituto Italiano di Tecnologia ; Sapienza University of Rome ; AFM-Telethon (grant 21025 ); and Italian Ministry of Education, Universities and Research, Dipartimenti di Eccellenza-L. ( 232/2016 ). Publisher Copyright: {\textcopyright} 2020 The Author(s) Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

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T1 - Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module

AU - Di Magno, Laura

AU - Manni, Simona

AU - Di Pastena, Fiorella

AU - Coni, Sonia

AU - Macone, Alberto

AU - Cairoli, Sara

AU - Sambucci, Manolo

AU - Infante, Paola

AU - Moretti, Marta

AU - Petroni, Marialaura

AU - Nicoletti, Carmine

AU - Capalbo, Carlo

AU - De Smaele, Enrico

AU - Di Marcotullio, Lucia

AU - Giannini, Giuseppe

AU - Battistini, Luca

AU - Goffredo, Bianca Maria

AU - Iorio, Egidio

AU - Agostinelli, Enzo

AU - Maroder, Marella

AU - Canettieri, Gianluca

N1 - Funding Information: We thank Ulupi Jhala and Rob Screaton for critical reading of the manuscript, editing, and discussion; Dr. Robert Wechsler-Reya for Math1-CRE;Ptch1 loxP/loxP mice; and Dr. Yoon-Jae Cho for Med1-MB cells. This work was supported by AIRC (grants IG 17575 and IG 20801 ); Istituto Pasteur, Fondazione Cenci-Bolognetti ; Fondazione Enrico ed Enrica Sovena ; Istituto Italiano di Tecnologia ; Sapienza University of Rome ; AFM-Telethon (grant 21025 ); and Italian Ministry of Education, Universities and Research, Dipartimenti di Eccellenza-L. ( 232/2016 ). Publisher Copyright: © 2020 The Author(s) Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/2/11

Y1 - 2020/2/11

N2 - The antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as model, we show here that at clinically relevant concentrations, phenformin elicits a significant therapeutic effect through a redox-dependent but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Because ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy.

AB - The antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as model, we show here that at clinically relevant concentrations, phenformin elicits a significant therapeutic effect through a redox-dependent but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Because ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy.

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KW - cancer

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KW - Hedgehog

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KW - phenformin

KW - redox

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