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

Animals Antineoplastic Agents / pharmacology Co-Repressor Proteins / drug effects Hedgehog Proteins / drug effects Humans Hypoglycemic Agents / pharmacology Mice Neoplasms / drug therapy Phenformin / pharmacology
CtBP2 Hedgehog NADH biguanides cancer complex I mGPD metformin phenformin redox

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
11 02 2020
Historique:
received: 24 05 2018
revised: 16 12 2019
accepted: 07 01 2020
entrez: 13 2 2020
pubmed: 13 2 2020
medline: 9 3 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2020.01.024 PMID: 32049007
pubmed: 32049007
pii: S2211-1247(20)30033-4
doi: 10.1016/j.celrep.2020.01.024
pii:
doi:

Substances chimiques

Antineoplastic Agents 0
Co-Repressor Proteins 0
Hedgehog Proteins 0
Hypoglycemic Agents 0
Phenformin DD5K7529CE

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1735-1752.e7

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

Auteurs

Laura Di Magno (L)

Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy.

Simona Manni (S)

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Fiorella Di Pastena (F)

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Sonia Coni (S)

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Alberto Macone (A)

Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, 00185 Rome, Italy.

Sara Cairoli (S)

Division of Metabolism and Research Unit of metabolic Biochemistry, Children's Hospital and Research Institute Bambino Gesù IRCCS, 00146 Rome, Italy.

Manolo Sambucci (M)

IRCCS Santa Lucia Foundation, Neuroimmunology Unit, 00143 Rome, Italy.

Paola Infante (P)

Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy.

Marta Moretti (M)

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Marialaura Petroni (M)

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Carmine Nicoletti (C)

Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, Sapienza University of Rome, 00161 Rome, Italy.

Carlo Capalbo (C)

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Enrico De Smaele (E)

Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Lucia Di Marcotullio (L)

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 (G)

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Luca Battistini (L)

IRCCS Santa Lucia Foundation, Neuroimmunology Unit, 00143 Rome, Italy.

Bianca Maria Goffredo (BM)

Division of Metabolism and Research Unit of metabolic Biochemistry, Children's Hospital and Research Institute Bambino Gesù IRCCS, 00146 Rome, Italy.

Egidio Iorio (E)

Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy.

Enzo Agostinelli (E)

Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, 00185 Rome, Italy; International Polyamines Foundation-ONLUS, 00159 Rome, Italy.

Marella Maroder (M)

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Gianluca Canettieri (G)

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. Electronic address: gianluca.canettieri@uniroma1.it.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Phenformin Inhibits Hedgehog-Dependent Tumor...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Phenformin Inhibits Hedgehog-Dependent Tumor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Protéines corépressives › Phenformin Inhibits Hedgehog-Dependent Tumor...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines Hedgehog › Phenformin Inhibits Hedgehog-Dependent Tumor...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Phenformin Inhibits Hedgehog-Dependent Tumor...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hypoglycémiants › Phenformin Inhibits Hedgehog-Dependent Tumor...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Phenformin Inhibits Hedgehog-Dependent Tumor...
questionsmedicales.fr › Tumeurs › Phenformin Inhibits Hedgehog-Dependent Tumor...
questionsmedicales.fr › Composés chimiques organiques › Amidines › Guanidines › Biguanides › Phenformine › Phenformin Inhibits Hedgehog-Dependent Tumor...