Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-23396-2
Keywords
-
Categories
Funding
- CIHR operating grants [111143, 244105]
- Quebec Breast Cancer Foundation
- Oncopole
- FRQS Reseau Recherche Cancer
- Terry Fox program project grant
- FRQS
- McGill's
- Fundacion para la Salud y la Educacion Dr. Salvador Zubiran
- FOINS-INCMNSZ postdoctoral fellowship [A-307-7]
- Diane and Sal Guerra Chair in Cancer Genetics at McGill University
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available