Cross-talk between the extrinsic and intrinsic cell death pathways

Molecular oncology. Causes of cancer and targets for treatment. Cambridge University Press (2014)


Under certain circumstances, extrinsic cell-death signaling may not be sufficient to trigger apoptosis, depending on the cell type (74–76). In type I cells (e.g. lymphocytes), sufficient activation of caspase-8 generated by large amounts of DISC directly activates downstream executioner caspases (e.g. caspase-3) and induces cell death. However, in type II cells (e.g. hepatocytes, pancreatic cells), DISC formation is not sufficient to trigger apoptotic death as only low amounts of caspse-8 are activated, not enough to transmit the apoptotic signals. In this case, the mitochondria-mediated intrinsic cell-death pathway is required to amplify the death signal to transmit the apoptotic signals (Figure 30.7).

Active caspase-8 cleaves and activates the downstream executioner caspases, but can also cleave other cellular substrates. One such target is the Bcl-2-family protein BID. Like many other Bcl-2-family members (77–78), BID is cleaved to generate a pro-apoptotic C-terminal fragment known as truncated BID (tBID; 79). tBID then causes mitochondrial outer membrane permeabilization (MOMP) by activating the pro-apoptotic Bcl-2 proteins BAX and BAK, while inhibiting anti-apoptotic Bcl-2-family members (Figure 30.7). BAX-induced pore formation in the outer membrane leads to release of pro-apoptotic proteins such as cytochrome c followed by a decrease in mitochondrial membrane potential (80–81). Cytosolic cytochrome c triggers activation and oligomerization of Apaf1 to form the apoptosome that recruits and activates the initiator caspase, caspase-9. In turn, caspase-9 cleaves and activates downstream executioner caspases such as caspase-3 (82). Caspase-3 is reported to cleave several hundred substrates at specific sites to cause apoptotic cell morphology and to dispose of the cell corpse. Cleavage of other Bcl-2 family proteins may also be involved, for example in T-cell development and activationinduced cell death (78).

Although extrinsic death signaling can induce intrinsic apoptosis in both type I and II cells, over-expression of antiapoptotic Bcl-2 proteins (e.g. Bcl-2 and Bcl-xL), which inhibit MOMP, are traditionally thought to only block apoptosis in type II cells, but not in type I cells. This suggests that the intrinsic cell-death pathway is essential for apoptosis in type II cells, while the intrinsic pathway serves as an amplifier in type I cells (83). However, the apoptosis functions of Bcl-2-family proteins at mitochondria may be only one of their functions contributing to cell death and survival. This is suggested by the conservation of Bcl-2-family proteins in species that are not known to undergo classic mitochondria-dependent apoptosis analogous to mammalian cells. New roles are being assigned to Bcl-2 family proteins in cellular energetics and autophagy in healthy cells prior to an apoptosis signal, and their detailed biochemical functions have not yet been delineated (84).

A recent study reveals an important role of mitochondria for caspase-8 activation in type II cells (85–86). Upon Fas activation, caspase-8 is translocated and embedded into the mitochondrial outer membrane by interacting with mitochondrial cardiolipin. Mitochondrial cardiolipin provides a platform for caspase-8 accumulation, oligomerization, and full activation, which is required for efficient apoptosis in type II cells.

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