4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-021-23396-2

Keywords

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Funding

  1. CIHR operating grants [111143, 244105]
  2. Quebec Breast Cancer Foundation
  3. Oncopole
  4. FRQS Reseau Recherche Cancer
  5. Terry Fox program project grant
  6. FRQS
  7. McGill's
  8. Fundacion para la Salud y la Educacion Dr. Salvador Zubiran
  9. FOINS-INCMNSZ postdoctoral fellowship [A-307-7]
  10. Diane and Sal Guerra Chair in Cancer Genetics at McGill University

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Bioenergetic perturbations and oxidative stress play important roles in promoting neoplastic growth, requiring compensatory increase in ROS scavengers. In addition, inflammatory mediators can enhance drug cytotoxicity through STAT1-mediated downregulation of ROS scavengers.
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 IFN gamma 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 beta -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. Complex I inhibition induces oxidative stress leading to cancer cell cytotoxicity. Here, the authors show, in breast cancer models, that inflammatory mediators can potentiate complex I inhibitor phenformin cytotoxicity through STAT1-mediated downregulation of the reactive oxygen species scavenger NQO1.

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