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

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Abstract

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.

Section snippets

Introduction: Apo2L/TRAIL and its receptors

Apo2L/TRAIL was originally identified and cloned based on sequence homology to the Fas/Apo1 ligand (FasL) and TNF [1], [2]. Subsequent work led to identification of four novel, closely related cell-associated members of the TNF receptor (TNFR) superfamily that bind this ligand, as well as a fifth, soluble receptor that is more distantly related to the other four. The nomenclature for Apo2L/TRAIL and its receptors is summarized in Table 1. Two of the receptors that bind Apo2L/TRAIL contain

The Apo2L/TRAIL DISC

Similar to FasL, Apo2L/TRAIL initiates apoptosis upon binding to its cognate death receptors by inducing the recruitment of specific cytoplasmic proteins to the intracellular death domain of the receptor, which form the death-inducing signaling complex (DISC; Fig. 2) [28]. In untransfected cells, the Apo2L/TRAIL DISC is similar to that of FasL, with the adaptor protein Fas-associated death domain (FADD, also called Mort-1 (Chapter by Genhong Chen; Reference—CGFR CHAPTER: cell death-death domain

Modulation of sensitivity to Apo2L/TRAIL

Numerous reports indicate that while many human tumor cell lines are sensitive to apoptosis induction by Apo2L/TRAIL, most normal cells are not. It is not completely clear why normal cells and certain tumor cells are resistant to Apo2L/TRAIL. Some of the potential mechanisms are discussed below.

Regulation of Apo2L/TRAIL expression by interferons

IFNs are a family of pleiotropic cytokines, which consist of Type I (predominantly α and β) and II (γ) IFNs. They play an essential role in host defense, having both anti-viral and anti-tumor effects. Induction of cell death was not initially recognized as a property of IFNs, as only a few reports of this activity were available [85], [86]. However, recent work demonstrates that IFNs can act as apoptosis-inducing cytokines on various cancer cell lines (reviewed in [87]), including multiple

Cancer therapeutic potential

Apoptosis induction in response to most DNA-damaging drugs usually requires the function of the tumor suppressor p53, which engages primarily the cell-intrinsic apoptotic-signaling pathway [36]. In most human cancers, following tumor progression or as a result of clinical treatments p53 is inactivated, resulting in resistance to further therapy. Death receptors can trigger apoptosis independently of p53, and therefore their targeting might be a useful therapeutic strategy, particularly in cells

Conclusions and future directions

Apo2L/TRAIL is a powerful inducer of apoptosis that acts through an unusually complex receptor system. Interferons are important modulators of Apo2L/TRAIL expression, and consistent with this finding, the ligand seems to play an important role in surveillance by cells of the innate immune system against viral-infection and malignant transformation of host cells. Because of the selectivity of soluble, Zn-bound Apo2L/TRAIL toward transformed versus normal cells, this protein bears exciting

Acknowledgements

Supported in part by research grants from the National Cancer Institute CA81504, CA82858 (A. Almasan).

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