TRAIL/Apo-2L: mechanisms and clinical applications in cancer

Abstract

TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) is a member of the TNF family that promotes apoptosis by binding to the transmembrane receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. Its cytotoxic activity is relatively selective to the human tumor cell lines without much effect on the normal cells. Hence, it exerts an antitumor activity without causing toxicity, as apparent by studies with several xenograft models. This review discusses the intracellular mechanisms by which TRAIL induces apoptosis. The major pathway of its action proceeds through the formation of DISC and activation of caspase-8. The apoptotic processes, therefore, follow two signaling pathways, namely the mitochondrial-independent activation of caspase-3, and mitochondrial-dependent apoptosis due to cleavage of BID by caspase-8, the formation of apoptosomes, and activation of caspase-9 and the downstream caspases. Bcl-2 and Bcl-X(L) have no effect on TRAIL-induced apoptosis in lymphoid cells, whereas these genes block or delay apoptosis in nonlymphoid cancer cells. TRAIL participates in cytotoxicity mediated by activated NK cells, monocytes, and some cytotoxic T cells. Hence, TRAIL may prove to be an effective antitumor agent. In addition, it may enhance the effectiveness of treatment with chemotherapeutic drugs and irradiation. Nontagged Apo-2L/TRAIL does not cause hepatotoxicity in monkeys and chimpanzees and in normal human hepatocytes. Thus, nontagged Apo-2L/TRAIL appears to be a promising new candidate for use in the treatment of cancer.

Figure 1

Schematic representation of TRAIL receptors and the components of TRAIL-DISC (death-inducing signaling complex). Trimerization of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5) initiates recruitment of adaptor protein FADD. It appears that a GTP-binding adaptor protein DAP3 couples TRAIL receptors to FADD. FADD contains a death effector domain (DD) that promotes recruitment of procaspase-8 to the DISC, by homotypic interactions between the DD present on FADD and procaspase-8. The induced proximity of procaspase-8 molecules is postulated to cause their activation by autocatalytic processes. RIP may also bind to these DR4 and DR5, initiating a cascade causing cell necrosis. Decoy receptors DcR1 and DcR2 lack death domains and do not induce apoptosis.

Figure 2

Intracellular mechanism of TRAIL-induced apoptosis. Apoptosis pathways activated by TRAIL and mitochondria are depicted. Ligation of death receptors by TRAIL leads to formation of DISC which in turn initiates two pathways: (a) activation of caspase-8 leading to apoptosis, and (b) activation of Bid to truncated Bid which in turn regulates mitochondrial functions. Cytochrome c along with Apaf-1 and dATP forms apoptosomes which activate caspase-9. Active forms of caspase-8 and -9 initiate a cascade of effector caspases such as caspase-3 and -7. Activated caspases cleaved several substrates leading to apoptosis. Bcl-2 and Bcl-X_L seem to delay or have no affect on apoptosis-related mitochondrial events. IAPs inhibit caspase-3, -7, and -9. Smac/DIABLO inhibits XIAP/cIAP.

Figure 3

Structure and function of XIAP. Functional domains of the XIAP protein. Baculoviral inhibitor of apoptosis repeat (BIR) domains is essential for the caspase-inhibitory function of XIAP. XIAP inhibits both the initiator caspase-9 and the effector caspase-3 and -7. XAF1, XIAP-associated factor 1. The function of the BIR1 domain of XIAP is still unclear.

Figure 4

Involvement of NFκB in TRAIL-induced apoptosis. Binding of death receptors DR4 and DR5 with ligand TRAIL results in the activation of NFκB. p50 and p65 subunits of NFκB are maintained in the cytoplasm by binding to IκB inhibitory proteins. In response to cellular stimulation, IκB proteins are phosphorylated (by IKK), ubiquitinated, and degraded. Removal of IκB from NFκB allows NFκB to translocate into the nucleus where it transactivates numerous apoptosis related genes such as c-IAPs, DR4, DR5, and Bcl-X_L.