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

Stephanie P Totten; Young Kyuen Im; Eduardo Cepeda Cañedo; Ouafa Najyb; Alice Nguyen; Steven Hébert; Ryuhjin Ahn; Kyle Lewis; Benjamin Lebeau; Rachel La Selva; Valérie Sabourin; Constanza Martínez; Paul Savage; Hellen Kuasne; Daina Avizonis; Nancy Santos Martínez; Catherine Chabot; Adriana Aguilar-Mahecha; Marie-Line Goulet; Matthew Dankner; Michael Witcher; Kevin Petrecca; Mark Basik; Michael Pollak; Ivan Topisirovic; Rongtuan Lin; Peter M Siegel; Claudia L Kleinman; Morag Park; Julie St-Pierre; Josie Ursini-Siegel

doi:10.1038/s41467-021-23396-2

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

Nat Commun. 2021 Jun 3;12(1):3299. doi: 10.1038/s41467-021-23396-2.

Authors

Stephanie P Totten^{1

2}, Young Kyuen Im^{1

2}, Eduardo Cepeda Cañedo¹, Ouafa Najyb^{3

4}, Alice Nguyen¹, Steven Hébert¹, Ryuhjin Ahn^{1

2}, Kyle Lewis^{1

2}, Benjamin Lebeau^{1

2}, Rachel La Selva^{1

2}, Valérie Sabourin¹, Constanza Martínez⁴, Paul Savage⁴, Hellen Kuasne⁴, Daina Avizonis⁴, Nancy Santos Martínez¹, Catherine Chabot¹, Adriana Aguilar-Mahecha¹, Marie-Line Goulet¹, Matthew Dankner^{2

4}, Michael Witcher^{1

2

5}, Kevin Petrecca⁶, Mark Basik^{1

2

5}, Michael Pollak^{1

2

5}, Ivan Topisirovic^{1

2

3

5}, Rongtuan Lin^{1

7}, Peter M Siegel^{2

3

4}, Claudia L Kleinman^{1

8}, Morag Park^{3

4

5}, Julie St-Pierre⁹, Josie Ursini-Siegel^{10

11

12

13}

Affiliations

¹ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
² Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
³ Department of Biochemistry, McGill University, Montreal, QC, Canada.
⁴ Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
⁵ Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
⁶ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
⁷ Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
⁸ Department Human Genetics, McGill University, Montreal, QC, Canada.
⁹ Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada.
¹⁰ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada. giuseppina.ursini-siegel@mcgill.ca.
¹¹ Division of Experimental Medicine, McGill University, Montreal, QC, Canada. giuseppina.ursini-siegel@mcgill.ca.
¹² Department of Biochemistry, McGill University, Montreal, QC, Canada. giuseppina.ursini-siegel@mcgill.ca.
¹³ Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada. giuseppina.ursini-siegel@mcgill.ca.

Abstract

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.

Publication types

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

MeSH terms

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

Substances

Antineoplastic Agents
Naphthoquinones
Reactive Oxygen Species
STAT1 Transcription Factor
STAT1 protein, human
beta-lapachone
Interferon-gamma
Phenformin
NAD(P)H Dehydrogenase (Quinone)
NQO1 protein, human
Electron Transport Complex I
Glutathione
Poly I-C

Abstract

Publication types

MeSH terms

Substances

Grants and funding