By Bethany Veo, PhD
Necroptosis occurs when cells fail to undergo apoptosis following inflammatory, oxidative or ischemic stressors. Necroptotic cell death removes damaged cells and cells no longer critical for development, independently of caspase activation. Whereas apoptotic cells display condensed nuclei and fragmentation, the telltale signs of necroptosis are plasma membrane permeabilization and mitochondria swelling. As a regulated cell death mechanism, the process of necroptosis is necessary for maintaining cellular homeostasis during development and as a response to cellular stress conditions.
Initiation of necroptosis results from blocking pro-survival cues from inhibitors of apoptosis. Signaling through TNFa (tumor necrosis factor), FASL (FAS ligand) and TRAIL (Tumor related apoptosis induced ligand) recruit RIP1 (receptor interacting protein I) into a complex with cellular inhibitors of apoptosis (cIAPs) at the plasma membrane. Normally this leads to a cascade of events which result in activation of NF-κB and promotion of cell survival. However, when this process is blocked, RIP1 forms a secondary complex containing activated caspase-8, inducing apoptosis. Conditions such as cellular stress, in which caspase-8 activity is inhibited, lead to the formation of the necrosome, switching RIP1's activity from apoptotic to necrotic.
In necroptosis, RIP3 is recruited into the necrosome where it is phosphorylated by RIP1. Activated RIP3 will then phosphorylate MLKL (mixed-linage kinase domain-like protein) which associates with additional MLKL proteins at the plasma membrane surface to create a pore. The MLKL pore disrupts the membrane surface, causing an influx of Ca2+ and Na+, release of mitochondrial DNA, IL-33, IL-1β, and ATP eventually leading to cell death. RIP3 and MLKL are essential mediators of necroptosis.
Necroptosis has both positive and negative physiological consequences. Like apoptosis, necroptosis plays a critical role in eliminating cells deemed unnecessary for normal physiological processes. In diseased physiological states, such as neurodegenerative conditions, often associated with oxidative stress, necroptosis may be triggered and induce neuronal cell death. Inhibition of necroptosis generally ameliorates signs of neurodegeneration in models of Alzheimer's and Huntington's disease.
In contrast, the role of necroptosis in cancer is less obvious. While necroptosis has been implicated in the inhibition of tumorigenesis and metastasis. For example, the deregulation of necroptosis has been implicated in the development of acute myeloid leukemia and ovarian carcinogenesis. For some cancer types, such as esophageal, pancreatic and colon cancers, contrary to a tumor suppressive phenotype, necroptosis is linked with enhancement of cancer progression and metastasis. How exactly necroptosis promotes tumorigenesis and metastasis is currently unknown. However, experts believe that necroptosis may contribute to carcinogenesis via the induction of reactive oxygen species, inflammation and reduction of immune responsiveness. In fact, RIP1 regulates the cell's inflammatory response due to TNF and TLR (toll like receptor) signaling. The activity of RIP1 can lead to gross inflammation, thus making diseases such as acute and chronic inflammation prime targets for RIP1 inhibition by necrostatin.
Undoubtedly, regulation of necroptosis has far-reaching effects in both maintaining cellular health and as a target for the treatment of disease. Continued development of inhibitors of RIP1, RIP3, and MLKL shows promise for disease treatment. Nevertheless, further research is needed to understand when necroptosis can be used to promote health versus promoting pathogenesis.
