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

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.

Gold(III)-P-chirogenic complex induces mitochondrial dysfunction in triple-negative breast cancer

“…However, to maintain tumor progression, these transformed cells have increased antioxidant pathways to attenuate the ROS-induced oxidative stress. Given that ROS can trigger programmed cell death, several studies in recent years have explored ROS-induced oxidative damage as a therapeutic approach to kill cancer cells ( Perillo et al., 2020 ; Totten et al., 2021 ). Depolarization of the mitochondria membrane potential is related to production of mitochondria reactive oxygen species (mtROS) ( Sundqvist et al., 2017 ; Vyssokikh et al., 2020 ; Zorov et al., 2014 ).…”

Myoferlin disturbs redox equilibrium to accelerate gastric cancer migration

“…Glutathione was a major ROS scavenger in cancer cells, being present in thiol reduced (GSH) and oxidized (GSSG) states, with GSH being predominant. NADPH was a crucial cofactor and electron donor that replenishes GSH levels and maintains redox balance ( 38 ). MYOF was found to alter the amounts of GSH and GSSG in gastric cancer cells, reducing the GSH/GSSG ratio in HGC27 and SNU1 cells (P<0.0001; Figures 5E ; Supplementary Figures 2E ).…”

Melatonin Prevents NaAsO2-Induced Developmental Cardiotoxicity in Zebrafish through Regulating Oxidative Stress and Apoptosis

“…Similar mechanisms for the effects on the organisms of other environmental compounds have been reported in recent studies [ 19 , 35 ]. However, oxygen free radicals play an indispensable role in the normal physiological processes of the body, and non-selective quenching of all free radicals in the cells may be harmful, but selectively scavenging or reducing the mitochondrial ROS production could be beneficial for the prevention and treatment of ROS-related diseases [ 36 , 37 ]. Various studies have shown that SIRT3, the most important deacetylase in mitochondria, is an effective intervention target for the prevention and treatment of oxidative stress-related diseases [ 38 , 39 ].…”