Ferroptosis

Brent Stockwell and Scott J. Dixon 2012

The term ferroptosis was coined in 2012 by Brent Stockwell and Scott J. Dixon. Ferroptosis refers to a particular form of programmed cell death with special properties and recognition functions that play a role in physical conditions or various diseases, including malignant tumors. Ferroptosis is genetically and biochemically distinct from other forms of programmed cell death such as apoptosis, although overlap also exists between ferroptosis and apoptosis. For example, the canonical tumor suppressor protein P53 can not only prevent tumorigenesis by arresting the cell cycle and triggering apoptosis, but also trigger ferroptosis under certain conditions (Zheng DW et al. 2017).

The main feature of ferroptosis is the iron-dependent accumulation of oxidatively damaged phospholipids (i.e. lipid peroxides). This occurs when free radicals remove electrons from a lipid molecule (which usually affects polyunsaturated fatty acids), thereby promoting their oxidation. Lipophilic antioxidants and iron chelators can prevent the ferroptotic cell death.

Ferroptosis is triggered by the failure of glutathione-dependent antioxidant defenses. This leads to uncontrolled lipid peroxidation, consequently to the accumulation of lipid peroxides and finally to cell death. Some molecules regulating ferroptosis are involved in metabolic pathways regulating cysteine utilization, glutathione status, nicotinamide adenine dinucleotide phosphate function, lipid peroxidation, and iron homeostasis. Furthermore, iron metabolism-related genes such as transferrin (TF), transferrin receptor 1 (TFR1), ferroportin (FPN), divalent metal transporter 1 (DMT1), ferritin heavy chain 1 (FTH1), and ferritin light chain (FTL) are important mediators in ferroptosis.

Oncologically significant, activation of ras-mitogen-activated protein kinase(MEK) signaling can increase the sensitivity of cancer cells to ferroptosis. The explanation is that it promotes iron abundance in cancer cells by controlling the expression level of the transferrin receptor and ferritin (Yagoda N et al. 2007).

The morphological changes that the cells undergo during ferroptosis can be observed by "live cell imaging". Initially, the cell contracts and then begins to swell. Immediately before the onset of ferroptosis, perinuclear lipid accumulation is observed. After the process is complete, the lipid droplets are redistributed throughout the cell.

Numerous studies suggest that ferroptosis is an adaptive process that may be critical for the elimination of carcinogenic cells (Dixon SJ 2017).

Ferroptosis is significantly more immunogenic than apoptosis. This is based on the release of damage-associated molecular patterns(DAMPs), inducing a pro-inflammatory process. This process induces chemoattractive signals that attract and activate immune cells. This explains why ferroptosis inducers become effective as a suitable enhancer for anti-tumor immunotherapy, e.g. checkpoint inhibitors (Ahern TP et al. 2014).

Ferroptosis inducers are small molecules such as erastin, sulfasalazine and sorafenib. They inhibit tumor cell growth by inducing ferroptosis.

Recent research shows that SOCS1 is required for p53 activation and regulation of cellular senescence. SOCS1 can regulate the expression of p53 target genes by, for example, reducing the expression of the cystine transporter SLC7A and glutathione levels, thereby sensitizing cells to ferroptosis (Saintgermain E et al. 2017).

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