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

L. Di Magno, S. Manni, F. Di Pastena, S. Coni, A. Macone, S. Cairoli, M. Sambucci, P. Infante, M. Moretti, M. Petroni, C. Nicoletti, C. Capalbo, E. De Smaele, L. Di Marcotullio, G. Giannini, L. Battistini, B.M. Goffredo, E. Iorio, E. Agostinelli, M. MaroderG. 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. © 2020 The Author(s) 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. © 2020 The Author(s)
Original languageEnglish
Pages (from-to)1735
JournalCell Rep.
Volume30
Issue number6
DOIs
Publication statusPublished - 2020

Keywords

  • biguanides
  • cancer
  • complex I
  • CtBP2
  • Hedgehog
  • metformin
  • mGPD
  • NADH
  • phenformin
  • redox
  • binding protein
  • C terminal binding protein 1
  • glycerol 3 phosphate dehydrogenase
  • reduced nicotinamide adenine dinucleotide
  • sonic hedgehog protein
  • transcription factor Gli1
  • unclassified drug
  • animal tissue
  • antineoplastic activity
  • Article
  • bioaccumulation
  • C57BL 6 mouse
  • cancer inhibition
  • clinical effectiveness
  • controlled study
  • dose response
  • drug effect
  • drug efficacy
  • drug mechanism
  • drug structure
  • female
  • mouse
  • nonhuman
  • oxidation reduction state
  • priority journal
  • SCID mouse
  • signal transduction
  • tumor volume

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