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

Laura Di Magno¹, Simona Manni², Fiorella Di Pastena², Sonia Coni², Alberto Macone³, Sara Cairoli⁴, Manolo Sambucci⁵, Paola Infante¹, Marta Moretti², Marialaura Petroni², Carmine Nicoletti⁶, Carlo Capalbo², Enrico De Smaele⁷, Lucia Di Marcotullio⁸, Giuseppe Giannini², Luca Battistini⁵, Bianca Maria Goffredo⁴, Egidio Iorio⁹, Enzo Agostinelli¹⁰, Marella Maroder², Gianluca Canettieri¹¹

Affiliations

¹ Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy.
² Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
³ Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, 00185 Rome, Italy.
⁴ Division of Metabolism and Research Unit of metabolic Biochemistry, Children's Hospital and Research Institute Bambino Gesù IRCCS, 00146 Rome, Italy.
⁵ IRCCS Santa Lucia Foundation, Neuroimmunology Unit, 00143 Rome, Italy.
⁶ Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University of Rome, 00161 Rome, Italy.
⁷ Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
⁸ Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00161 Rome, Italy.
⁹ Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy.
¹⁰ Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, 00185 Rome, Italy; International Polyamines Foundation-ONLUS, 00159 Rome, Italy.
¹¹ Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00161 Rome, Italy; International Polyamines Foundation-ONLUS, 00159 Rome, Italy. Electronic address: gianluca.canettieri@uniroma1.it.

PMID: 32049007
DOI: 10.1016/j.celrep.2020.01.024

Free article

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

Laura Di Magno et al. Cell Rep. 2020.

Free article

. 2020 Feb 11;30(6):1735-1752.e7.

doi: 10.1016/j.celrep.2020.01.024.

Authors

Affiliations

¹ Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy.
² Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
³ Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, 00185 Rome, Italy.
⁴ Division of Metabolism and Research Unit of metabolic Biochemistry, Children's Hospital and Research Institute Bambino Gesù IRCCS, 00146 Rome, Italy.
⁵ IRCCS Santa Lucia Foundation, Neuroimmunology Unit, 00143 Rome, Italy.
⁶ Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University of Rome, 00161 Rome, Italy.
⁷ Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
⁸ Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00161 Rome, Italy.
⁹ Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy.
¹⁰ Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, 00185 Rome, Italy; International Polyamines Foundation-ONLUS, 00159 Rome, Italy.
¹¹ Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00161 Rome, Italy; International Polyamines Foundation-ONLUS, 00159 Rome, Italy. Electronic address: gianluca.canettieri@uniroma1.it.

PMID: 32049007
DOI: 10.1016/j.celrep.2020.01.024

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: CtBP2; Hedgehog; NADH; biguanides; cancer; complex I; mGPD; metformin; phenformin; redox.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases