Activation of apoptosis in NAF-1-deficient human epithelial breast cancer cells

Abstract

Maintaining iron and reactive oxygen species homeostasis is essential for cellular function, mitochondrial integrity and the regulation of cell death pathways, and is recognized as a key process underlying the molecular basis of aging and various diseases such as diabetes, neurodegenerative diseases, and cancer. Nutrient-deprivation autophagy factor 1 (NAF-1) belongs to a newly discovered class of iron-sulfur proteins localized to the outer mitochondrial membrane and the ER. It has been implicated in regulating iron homeostasis, as well as the activation of autophagy via interaction with BCL-2. Here we show that shRNA suppression of NAF-1 results in the activation of apoptosis in epithelial breast cancer cells and xenograft tumors. Suppression of NAF-1 resulted in increased iron uptake into cells, a metabolic shift that rendered cells more susceptible to a glycolysis inhibitor, and the activation of cellular stress pathways associated with HIF1α. Our studies suggest that NAF-1 is a major player in the metabolic regulation of breast cancer cells through its effects on cellular iron distribution, mitochondrial metabolism and the induction of apoptosis.