| Literature DB >> 32049007 |
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.
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.Entities:
Keywords: CtBP2; Hedgehog; NADH; biguanides; cancer; complex I; mGPD; metformin; phenformin; redox
Mesh：
Substances：
Year: 2020 PMID： 32049007 DOI： 10.1016/j.celrep.2020.01.024
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423