@article{215d858a5f124c53b6c6389547473236,
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.",
year = "2020",
month = feb,
day = "11",
doi = "10.1016/j.celrep.2020.01.024",
language = "English",
volume = "30",
pages = "1735--1752.e7",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}