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
Affiliations
Laura Di Magno
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy
Simona Manni
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Fiorella Di Pastena
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Sonia Coni
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Alberto Macone
Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, 00185 Rome, Italy
Sara Cairoli
Division of Metabolism and Research Unit of metabolic Biochemistry, Children’s Hospital and Research Institute Bambino Gesù IRCCS, 00146 Rome, Italy
Manolo Sambucci
IRCCS Santa Lucia Foundation, Neuroimmunology Unit, 00143 Rome, Italy
Paola Infante
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy
Marta Moretti
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Marialaura Petroni
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Carmine Nicoletti
Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University of Rome, 00161 Rome, Italy
Carlo Capalbo
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Enrico De Smaele
Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
Lucia Di Marcotullio
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00161 Rome, Italy
Giuseppe Giannini
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Luca Battistini
IRCCS Santa Lucia Foundation, Neuroimmunology Unit, 00143 Rome, Italy
Bianca Maria Goffredo
Division of Metabolism and Research Unit of metabolic Biochemistry, Children’s Hospital and Research Institute Bambino Gesù IRCCS, 00146 Rome, Italy
Egidio Iorio
Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy
Enzo Agostinelli
Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, 00185 Rome, Italy; International Polyamines Foundation-ONLUS, 00159 Rome, Italy
Marella Maroder
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Gianluca Canettieri
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; Corresponding author
Summary: 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. : Di Magno et al. investigate the therapeutic properties of phenformin in Hedgehog-dependent tumors. At clinically relevant doses, phenformin works independent of respiratory complex I through mGPD-mediated increase of the redox state. This promotes CtBP2/Gli1 complex formation and consequent inhibition of Hedgehog transcriptional output and tumor growth. Keywords: phenformin, cancer, Hedgehog, complex I, mGPD, NADH, CtBP2, metformin, redox, biguanides
