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

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23396-2

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DOI: 10.1038/s41467-021-23396-2

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