NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis

Abstract

Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality1,2. Here, using loss-of-function screening based on RNA interference, we show that environmental oxygen levels are a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3–8% oxygen concentration typical of most tissues, we find that cancer cells depend on high levels of the iron–sulfur cluster biosynthetic enzyme NFS1. Mammary or subcutaneous tumours grow despite suppression of NFS1, whereas metastatic or primary lung tumours do not. Consistent with a role in surviving the high oxygen environment of incipient lung tumours, NFS1 lies in a region of genomic amplification present in lung adenocarcinoma and is most highly expressed in well-differentiated adenocarcinomas. NFS1 activity is particularly important for maintaining the iron–sulfur co-factors present in multiple cell-essential proteins upon exposure to oxygen compared to other forms of oxidative damage. Furthermore, insufficient iron–sulfur cluster maintenance robustly activates the iron-starvation response and, in combination with inhibition of glutathione biosynthesis, triggers ferroptosis, a nonapoptotic form of cell death. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage.

Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress

“…For example, mitochondrial Fe-S cluster biosynthesis is a process that is highly conserved in eukaryotic organisms from yeast to man (Lill and Muhlenhoff, 2006). In cancer cells, it has been reported that this biosynthetic pathway is essential for proliferation in the OXPHOS state (Arroyo et al, 2016) and for primary lung or metastatic tumors growing in high oxygen levels (Alvarez et al, 2017). This could be largely due to the numerous mitochondrial proteins that depend on Fe-S clusters for their functionality including complex I-III proteins, ACO1 and others making it a key upstream regulator of mitochondrial function (Cameron et al, 2011).…”

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

“…Accordingly, lipid peroxidation and ferroptotic cell death induced by perturbation of glutathione metabolism or GPX4 activity are fully suppressed by iron chelators like deferoxamine (DFO) and ciclopirox (CPX) . Disruption of the iron‐sulfur cluster biogenesis pathway enzyme cysteine desulfurase NFS1 sensitizes to ferroptosis in cultured cancer cells and in xenograft tumor models, most likely, by increasing the pool of free iron within the cell . Normally, iron is imported into the cell via the transferrin/transferrin receptor system and liberated from transferrin within lysosomes.…”

Ferritinophagy/ferroptosis: Iron‐related newcomers in human diseases

“…is suppressed by N-ethylmaleimide-sensitive fusion protein 1, an iron-sulfur cluster biosynthetic enzyme, thereby resisting against high oxygen tension and inducing lung tumor growth(Alvarez et al, 2017). Ferrostatin-1, as another ferroptosis inhibitor, remarkably impedes ART-induced ROS production and ferroptosis-dependent cell death in ovarian cancer(Basuli et al, 2017;Greenshields, Shepherd, & Hoskin, 2017).…”