STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer.

Animals Antineoplastic Agents / administration & dosage Breast Neoplasms / drug therapy Cell Line, Tumor Drug Synergism Electron Transport Complex I / antagonists & inhibitors Energy Metabolism / drug effects Female Glutathione / antagonists & inhibitors Humans Interferon-gamma / administration & dosage MCF-7 Cells Mammary Neoplasms, Experimental / drug therapy Mice Mice, Inbred BALB C Mice, Knockout Mice, SCID NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors Naphthoquinones / administration & dosage Oxidative Stress / drug effects Phenformin / administration & dosage Poly I-C / administration & dosage Reactive Oxygen Species / metabolism STAT1 Transcription Factor / agonists Xenograft Model Antitumor Assays

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
03 06 2021

Historique:

received: 01 07 2020

accepted: 28 04 2021

entrez: 4 6 2021

pubmed: 5 6 2021

medline: 12 6 2021

Statut: epublish

Résumé

Bioenergetic perturbations driving neoplastic growth increase the production of reactive oxygen species (ROS), requiring a compensatory increase in ROS scavengers to limit oxidative stress. Intervention strategies that simultaneously induce energetic and oxidative stress therefore have therapeutic potential. Phenformin is a mitochondrial complex I inhibitor that induces bioenergetic stress. We now demonstrate that inflammatory mediators, including IFNγ and polyIC, potentiate the cytotoxicity of phenformin by inducing a parallel increase in oxidative stress through STAT1-dependent mechanisms. Indeed, STAT1 signaling downregulates NQO1, a key ROS scavenger, in many breast cancer models. Moreover, genetic ablation or pharmacological inhibition of NQO1 using β-lapachone (an NQO1 bioactivatable drug) increases oxidative stress to selectively sensitize breast cancer models, including patient derived xenografts of HER2+ and triple negative disease, to the tumoricidal effects of phenformin. We provide evidence that therapies targeting ROS scavengers increase the anti-neoplastic efficacy of mitochondrial complex I inhibitors in breast cancer.

Identifiants

DOI: 10.1038/s41467-021-23396-2 PMID: 34083537 PMC: PMC8175605

pubmed: 34083537

doi: 10.1038/s41467-021-23396-2

pii: 10.1038/s41467-021-23396-2

pmc: PMC8175605

doi:

Substances chimiques

Antineoplastic Agents 0

Naphthoquinones 0

Reactive Oxygen Species 0

STAT1 Transcription Factor 0

STAT1 protein, human 0

beta-lapachone 6N4FA2QQ6A

Interferon-gamma 82115-62-6

Phenformin DD5K7529CE

NAD(P)H Dehydrogenase (Quinone) EC 1.6.5.2

NQO1 protein, human EC 1.6.5.2

Electron Transport Complex I EC 7.1.1.2

Glutathione GAN16C9B8O

Poly I-C O84C90HH2L

Types de publication

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

Langues

eng

Sous-ensembles de citation

Pagination

3299

Subventions

Organisme : CIHR

ID : 111143

Pays : Canada

Organisme : CIHR

ID : 244105

Pays : Canada

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