![]() The type of cell death activated by the RSLs has been enigmatic. ShRNA and cDNA overexpression studies demonstrated that VDAC2 and VDAC3 are necessary, but not sufficient, for erastin-induced death ( Yagoda et al., 2007), indicating that additional unknown targets are required for this process. Using affinity purification, we identified voltage dependent anion channels 2 and 3 (VDAC2/3) as direct targets of erastin ( Yagoda et al., 2007), but not RS元. We previously identified two structurally unrelated small molecules, named erastin and RS元, that were selectively lethal to oncogenic RAS-mutant cell lines, and which we refer to together as RAS-selective lethal (RSL) compounds ( Dolma et al., 2003 Yang and Stockwell, 2008). Finding compounds that are selectively lethal to RAS-mutant tumor cells is therefore a high priority. The RAS family small GTPases (HRAS, NRAS and KRAS) are mutated in ~30% of all cancers ( Vigil et al., 2010). We hypothesized that additional regulated forms of non-apoptotic cell death likely remain to be discovered that mediate cell death in other developmental or pathological circumstances. ![]() More recently this view has been challenged by the discovery of several regulated non-apoptotic cell death pathways activated in specific disease states, including poly(ADP-ribose) polymerase-1 (PARP-1) and apoptosis inducing factor 1 (AIF1)-dependent parthanatos, caspase-1-dependent pyroptosis and receptor interacting protein kinase 1 (RIPK1)-dependent necroptosis ( Bergsbaken et al., 2009 Christofferson and Yuan, 2010 Wang et al., 2009). It was once thought that almost all regulated cell death in mammalian cells resulted from the activation of caspase-dependent apoptosis ( Fuchs and Steller, 2011 Thompson, 1995). Thus, activation of ferroptosis results in the non-apoptotic destruction of certain cancer cells, while inhibition of this process may protect organisms from neurodegeneration.Ĭell death is crucial for normal development, homeostasis and the prevention of hyper-proliferative diseases such as cancer ( Fuchs and Steller, 2011 Thompson, 1995). Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x c −), creating a void in the antioxidant defenses of the cell, ultimately leading to iron-dependent, oxidative death. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically and genetically distinct from apoptosis, necrosis and autophagy. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of non-apoptotic cell death that we term ferroptosis. Non-apoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states.
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