Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy

Apo2 ligand or tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) is one of several members of the TNF gene superfamily that induce apoptosis through engagement of death receptors. Apo2L/TRAIL is unusual as compared to any other cytokine as it interacts with a complex system of receptors: two pro-apoptotic death receptors and three anti-apoptotic decoys. This protein has generated tremendous excitement as a potential tumor-specific cancer therapeutic because, as a stable soluble trimer, it selectively induces apoptosis in many transformed cells but not in normal cells. Transcriptional activation of Apo2L/TRAIL by interferons (IFNs) through specific regulatory elements in its promoter, and possibly by a number of other cytokines, reveals its possible involvement in the activation of natural killer cells, cytotoxic T lymphocytes, and dendritic cells. In this review, we focus on the apoptosis signaling pathways stimulated by Apo2L/TRAIL, summarize what is known to date about the physiological role of this ligand and the potential for its application to cancer therapy.