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 journalArticlepeer-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 languageEnglish
Pages (from-to)1735-1752.e7
JournalCell Reports
Volume30
Issue number6
DOIs
Publication statusPublished - 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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