Apo2L/TRAIL: apoptosis signaling, biology, and potential for 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).
References (126)
- et al.
Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family
J. Biol. Chem.
(1996) - et al.
Identification and characterization of a new member of the TNF family that induces apoptosis
Immunity
(1995) - et al.
TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL
Curr. Biol.
(1997) - et al.
Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL
J. Biol. Chem.
(1997) - et al.
Death receptor 5, a new member of the TNFR family and DR4 induce FADD-dependent apoptosis, and activate the NF-kappaB pathway
Immunity
(1997) - et al.
Characterization of two receptors for TRAIL
FEBS Lett.
(1997) - et al.
A novel receptor for Apo2L/TRAIL contains a truncated death domain
Curr. Biol.
(1997) - et al.
The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain
Immunity
(1997) - et al.
TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling
FEBS Lett.
(1998) - et al.
Osteoprotegerin: a novel secreted protein involved in the regulation of bone density
Cell
(1997)