Caspase‐8: regulating life and death

Abstract

Summary Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Whereas excessive cell damage results in passive necrosis, cells can be triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best-known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor-mediatedactivation of programmed cell death is the aspartate-specific cysteine protease (caspase)-8. This review describes the role of caspase-8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase-8 inhibits necroptosis. The importance of caspase-8 in development and homeostasis and the way that dysfunctional caspase-8 may contribute to the development of malignancies in mice and humans are also explored.

Induction of apoptosis by ethanol extract of <i>Citrus unshiu</i> Markovich peel in human bladder cancer T24 cells through ROS-mediated inactivation of the PI3K/Akt pathway

“…The release of cytochrome c requires insertion of mitochondrial membrane and oligomerization of Bax, which is a pro-apoptotic protein belonging to the Bcl-2 family. Thus, the increase in Bax protein expression plays an important role in the activation of the intrinsic pathway, and Bcl-2 is a typical anti-apoptotic protein that suppresses this process (10,11).…”

“…Among them, apoptosis, the most typical cell death mechanism, can be triggered through either a death receptor (DR)-initiated extrinsic pathway or a mitochondria-mediated intrinsic pathway characterized by the activation of common caspases (7,8). The extrinsic pathway triggers apoptosis through the binding of death ligands to the DRs, which activates the caspase cascade from the upstream initiator caspase-8 to the downstream effector caspases, including caspase-3 and -7, by recruiting adapter molecules (9,10). The intrinsic pathway is mainly regulated by the interaction between the Bcl-2 family of proteins composed of proteins capable of promoting or inhibiting apoptosis, which is also associated with impaired mitochondrial function.…”

Necroptotic cell death in anti‐cancer therapy

“…Notably, triggering TNFR1 leads to the induction of necroptosis only when apoptosis signaling is blocked (e.g. when caspase‐8 or apoptosis inhibitors [IAPs] are downregulated or inhibited) …”

“…However, a regulated type of necrosis (necroptosis) has been revealed thanks to the identification of chemical inhibitors of necrotic cell death (necrostatins), which underline its regulated nature (Table ) . It has been established that necroptosis is different from apoptosis and that it is regulated by receptor interacting protein kinase‐1 (RIPK1), RIPK3, and mixed lineage kinase domain‐like (MLKL) . Other necrotic cell death modalities that come under the umbrella term of regulated necrosis are ferroptosis and pyroptosis (Table ).…”

Regulation of B‐lineage cells by caspase 6

“…13,14 Depending on the cell type and levels of adaptors like FADD and cFLIP L , Casp8 can regulate the production of IL-1β, prosurvival pathways or necroptosis mediated by the receptor-interacting protein kinases-1 (RIPK1) and RIPK3 pathway. 14,15 Casp8 is also essential for hematopoietic progenitor cell proliferation and the differentiation of macrophages. 16 In B cells, Casp8 controls activation by TLR agonists and germinal center responses, 17,18 while Casp3 regulates B-cell activation in part by cleaving its substrate, the cell cycle inhibitor p21Cip1.…”