Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death

Department of Biological Sciences, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, NY 10027, USA.
Cell (Impact Factor: 32.24). 05/2012; 149(5):1060-72. DOI: 10.1016/j.cell.2012.03.042
Source: PubMed


Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. 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. 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 and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration.

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Available from: Darpan Patel, Mar 30, 2014
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    • "We found that one compound, NSC704397, was commercially available , and that it induces lethality in ferroptosis-susceptible HT- 1080 fibrosarcoma cells, which was suppressed by 100 mM a-tocopherol (Figure S3). We previously showed that lipophilic antioxidants such as a-tocopherol uniquely suppressed ferroptotic cell death among various oxidative cell death stimuli, strongly suggesting that NSC704397 induces ferroptosis (Dixon et al., 2012). Thus, this confirms that our cluster analysis is an effective approach to uncover MoA of lethal compounds systematically , and that the compound cluster we focused on represents ferroptosis inducers. "
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    • "However, it is also possible that different ROS-generating systems lead to different responses; for example, mitochondrial ROS may be more likely to promote damage and death (Giulivi et al. 1995; Heales et al. 1999; Adam-Vizi and Chinopoulos 2006; Abramov et al. 2007), while membrane-generated ROS is more often described as contributing to signaling for cell proliferation (Vilhardt and van Deurs 2004; Choi et al. 2005; Li et al. 2006; Ushio-Fukai 2006). These distinctions are clearly not absolute; mitochondrial ROS has also been shown to contribute to proliferation, tumorigenicity, migration, and metastasis (Lee et al. 2002; Kwon et al. 2004; Weinberg et al. 2010; Porporato et al. 2014), while NOX-generated ROS at the membrane can induce cell death through ferroptosis and necrosis (Kim et al. 2007; Dixon et al. 2012). Taken together, it seems likely that the cell response to ROS reflects a complex integration of ROS type, location, and level. "
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