Cancer Cells Can Undergo Iron-Dependent Nonapoptotic Cell Death

Multiple types of nonapoptotic cell death, including necrosis and autophagy, facilitate selective cell elimination in the absence of canonical apoptotic features. Dixon and colleagues characterize an additional form of nonapoptotic cell death induced by small molecules that are selectively lethal to RAS-mutant tumor cells. This iron-dependent process, named ferroptosis, is marked by increased levels of cytosolic and lipid reactive oxygen species (ROS) and abnormally small mitochondria with increased membrane density. Morphologic changes characteristic of apoptosis, necrosis, and autophagy did not occur during ferroptosis, and small-molecule inhibitors known to inhibit these cell death processes did not significantly affect ferroptosis. Additionally, the group of genes necessary for ferroptosis did not significantly overlap with the set of genes required for apoptosis. Together, these data indicate that ferroptosis is morphologically, biochemically, and genetically distinct from other known forms of cell death. Instead, RAS-mutant–selective lethal compounds such as erastin and sulfasalazine (SAS) were found to block cystine uptake by system x^–_c, an Na⁺-independent cystine/glutamate antiporter, which consequently inhibits synthesis of the antioxidant glutathione and disrupts cellular redox regulation. ROS-generating nicotinamide adenine dinucleotide phosphate oxidases, which are commonly upregulated in RAS-mutant tumors, then contribute to lethal ROS accumulation following inhibition of cystine uptake. These findings suggest that certain tumors may be primed for ferroptotic cell death when cystine uptake is disrupted. Furthermore, small-molecule inducers of ferroptosis, such as SAS, which is already approved by the U.S. Food and Drug Administration for treatment of ulcerative colitis and rheumatoid arthritis, may be worthy of investigation in patients with RAS-mutant tumors.

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012;149:1060–72.

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