SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  7. CONCLUSION
  8. Acknowledgements
  9. LITERATURE CITED

Tumor necrosis factor (TNF) is a cytokine that mediates tumor necrosis. To date, 20 different members of the TNF super-family and 21 different receptors have been identified. All ligands of the TNF super-family have been found to activate transcription factor NF-κB and c-Jun kinase. Members of this family have diverse biological effects, including induction of apoptosis, promotion of cell survival, and regulation of the immune system and hematopoiesis. The current review focuses on the biological effects of TNF-related apoptosis-inducing ligand (TRAIL), a TNF super-family member which, a few years ago, generated considerable enthusiasm for its anticancer activity, not accompanied by general toxicity in most normal tissues and organs. © 2004 Wiley-Liss, Inc.


Molecular structure and receptors

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  7. CONCLUSION
  8. Acknowledgements
  9. LITERATURE CITED

The story of TNF-related apoptosis-inducing ligand (TRAIL) begins when a new member of the super-family of tumor necrosis factor (TNF) capable of inducing apoptosis was identified and characterized (Wiley et al., 1995) by virtue of its sequence homology to CD95/Fas/Apo1 Ligand (FasL) and TNF. This protein was independently discovered by another group of investigators and named Apo2L (Pitti et al., 1996). TRAIL/Apo2L consists of 281–291 aa in the human and murine forms, respectively, which share 65% aa identity. TRAIL has the characteristics of a type II membrane protein, i.e., no leader sequence and an internal trans-membrane domain, and its extra-cellular region forms a soluble molecule upon proteolytic cleavage (Mariani and Krammer, 1998). To determine where the TRAIL gene resides in the human genome, in an initial study Wiley et al. (1995) analyzed metaphase chromosomes from two normal males by fluorescent in situ hybridization, observing that it is located on chromosome 3 at position 3q26 most likely in the region q26.1-q26.2. Later on, the human TRAIL/Apo2L gene was better characterized concerning both its structure and regulation as reported in Gong and Almasan (2000). Like other TNF family ligands (TNFα and β, lymphotoxin α and β, CD95/Fas/Apo1, etc.), TRAIL has an N-terminal (cytoplasmic) domain, which is not conserved across family members, while the C-terminal (extracellular) domain shows significant conservation and is sufficient for biological activity (Smith et al., 1994). Among the structurally related proteins belonging to the TNF family of cytokines (Gruss and Dower, 1995; Baker and Reddy, 1996), TRAIL shares the highest amino acid identity with CD95L (Wiley et al., 1995; Mariani and Krammer, 1998). What immediately distinguished TRAIL from CD95L and TNFα was its ability to induce apoptosis on various continuous cell lines and primary tumor cells (Walczak and Krammer, 2000), displaying minimal or no toxicity on most normal cells and tissues (reviewed in Ashkenazi and Dixit, 1999).

To facilitate biological studies, an epitope-tagged soluble form of TRAIL was constructed and identified by SDS–PAGE with an apparent molecular weight of 28 kDa (Wiley et al., 1995). Gel filtration analysis of the purified soluble TRAIL disclosed that the native molecule was multimeric in solution with a size of ∼80 kDa. Since then, a lot of recombinant TRAIL preparations have been obtained (Marsters et al., 1996; Pitti et al., 1996; Ashkenazi et al., 1999; Walczak et al., 1999) and commercialized so that the variety of techniques of construction/purification employed may justify some data inconsistencies (for details see LeBlanc and Ashkenazi, 2003). However, both full-length cell surface expressed TRAIL and picomolar concentrations of the soluble form rapidly induce apoptosis in a wide variety of transformed cell lines of diverse origin (Table 1).

Table 1. List of cell lines and primary cells sorted according to their different TRAIL sensitivity
 SensitiveResistantReferences
  1. Immortalized non transformed breast epithelial cell lines.

Cell lines   
 Neuroblastoma SK-N-MC* Milani et al. (2003)
 Non-small cell lung cancer NSCLC* Spierings et al. (2003)
 Human oral squamous cell carcinomas  Fukuda et al. (2003)
  HSC-2*  
  HSC-3*  
  HSC-4*  
  Ca9-22*  
  KB*  
 Human hepatocellular carcinoma HCC  Evi-Cheol et al. (2002)
  Hep G2 * 
  Hep G 2.2.15 * 
  Hep 3B * 
  PLC/PRF/5*  
  SNU-182 * 
  SNU-354 * 
  SNU-368*  
  SNU-387*  
  SNU-398 * 
  SNU-449 * 
  MCF 7*  
  HeLa*  
 Human B-cells pancreatic CM* Ou et al. (2002)
  HP62*  
 Human colon carcinomas  Tillman et al. (2003)
  GC (3)/cl**  
  VRC(5)/cl**  
  HCT 116**  
  HT 29*  
  RKO * 
  HCT 8 * 
 Human colon cancer cell SW480* Xu et al. (2003)
 Colon carcinoma cell lines  Van Geelen et al. (2003)
  CaCo-2 * 
  Colo 320 * 
  SW948*  
 Prostate cancer lines  Nesterov et al. (2001)
  ALVA-31**  
  PC-3**  
  DU 145**  
  TSU-Pr1*  
  SCA-1*  
  LNCaP * 
 Human Adenocarcinoma Cervix HeLa *Bernard et al. (2001)
 HCT 116* Wen et al. (2000)
 Breast normal °  Keane et al. (1999)
  MCF 10A*  
  184B5 * 
 Breast cancer   
  ZR 75-1 * 
  MCF-7 * 
  MDA-MB-231*  
  MDA-MB-453 * 
  MDA-MB-468 * 
  MDA-MB-157 * 
  ShBr-3 * 
 Osteogenic sarcoma  Evdokion et al. (2002)
  BTK-143*  
  HOS * 
  MG-63 * 
  SSSA-1 * 
  G-292 * 
  SAOS 2 * 
 Sarcoma RPMI-8826* Suzuki et al. (2003)
 Mieloma MG-63 * 
 Melanoma cell lines   
  Me 4405* Zhang et al. (1999)
  Me 1007*  
  Me 10538*  
  MM 200*  
  Mel-LT* Zhang et al. (2000)
  Mel-FH*  
  Mel-MC*  
  Mel-AT*  
  Mel-RM*  
  Mel-SP*  
  SK-Mel-28*  
  Mel-SG*  
  Mel-CV*  
  Mel-RMU*  
 Human melanoma A375* Steven et al., 1995
 Murine fibroblast L929* Steven et al., 1995
 Burkitt lymphoma*  
  Bsab*  
  Ramos*  
  Raji*  
  Daudi*  
 Monocytic THP-1 * 
 Large cell aneuplastic lymphoma K229 * 
 Spontaneous B cell MP-1 * 
 Lymphoid cells  Martin et al. (2000)
 BL-60 (human B cell line)*  
 BSAB (human B cell line)*  
 CEM (human T cell line)*  
 CEM *Scaffidi et al. (1998)
 Histiocytic lymphoma U937* Steven et al., 1995
 Leukemia   
  Molt-4 *Lee et al. (2003)
  Jurkat* Lee et al. (2003)
   Martin et al. (2000)
   Scaffidi et al. (1998)
 Human HL-60* Secchiero et al. (2002)
 Erithroleukemia  Di Pietro et al. (2001)
  K562* Secchiero et al. (2002)
  HEL*  
  FRIEND*  
Primary cultures   
 Normal   
 Endothelial cells HUVEC *Zauli et al. (2003)
   Zhang et al. (2000)
 * Li et al. (2003)
 Endothelial cells from dermal microvessels*  
 Human bone cells NHB *Evdokion et al. (2002)
 CD34+ cells *Secchiero et al. (2002)
   Di Pietro et al. (2001)
 Foetal pancreas* Chen et al. (2003)
 Human pancreatic islet cells *Ou et al. (2002)
 Colonic epithelium *Strater et al. (2002)
 Human prostate ephitelium cells PrEC* Nesterow et al. (2002)
 Aorta smooth muscle cells * 
  * 
 Human articular chondrocytes* Pettersen et al. (2002)
 Human primary hepatocytes NHPHs *Lin et al. (2000)
 Thyroid tissues *Mitstedes et al. (2001)
 Human thymus organ culture HTOC* Simonet et al. (1997)
 Cervical epithelium *Ryu et al. (2000)
 Cancer   
 Human oral squamous cell carcinomas HOSSCCs* Fukuda et al. (2003)
 Neoplastic thyroid tissues* Mitstedes et al. (2001)
 Tumor cervical cells* Ryu et al. (2000)

Significant levels of TRAIL transcripts have been detected in many human tissues and expressed constitutively in some cell lines (Wiley et al., 1995; Pitti et al., 1996). Such a widespread distribution of TRAIL transcripts differs from that of FasL and suggests that TRAIL must not be cytotoxic to most tissues in vivo. To justify the ability of TRAIL of inducing apoptosis in many different types of cultured cells, it was hypothesized either that the TRAIL receptors were restricted in their distribution or that they acted to induce apoptosis only under certain restricted circumstances. Like most other TNF family members, Apo2L/TRAIL forms a homotrimer (Hymowitz et al., 1999), which triggers apoptosis through interaction with the death receptors DR4 (TRAIL-R1) (Pan et al., 1997a) and DR5 (TRAIL-R2) (Chaudhary et al., 1997; Pan et al., 1997b; Schneider et al., 1997a; Screaton et al., 1997; Sheridan et al., 1997; Walczak et al., 1997; Wu et al., 1997). On the other hand, antagonistic decoy receptors, DcR1 (TRAIL-R3) (Degli-Esposti et al., 1997a; Pan et al., 1997b; Schneider et al., 1997a; Sheridan et al., 1997), DcR2 (TRAIL-R4) (Marsters et al., 1997; Degli-Esposti et al., 1997b; Pan et al., 1998), and osteoprotegerin (OPG; TRAIL-R5) (Simonet et al., 1997; Emery et al., 1998) can compete with DR4 and DR5 for ligand binding, thus protecting many normal cell types from induction of apoptosis. More recent evidences, based on the use of monoclonal anti-TRAIL receptor antibodies instead of over-expression models, have pointed at the primary role of intracellular mechanisms in controlling TRAIL resistance in a number of cell types (Griffith et al., 1998; Zhang et al., 1999; Leverkus et al., 2000), thus cutting down the importance of control at decoy receptors level, whose biochemical function is still to be clarified.

Signaling pathways and genes activated

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  7. CONCLUSION
  8. Acknowledgements
  9. LITERATURE CITED

Although much effort has been made to elucidate the molecular mechanisms of TRAIL signaling, the components of different TRAIL signaling routes are still largely undefined. Instead, signaling pathways involved in the generation of TRAIL-induced apoptosis have been extensively reviewed (Walczak and Krammer, 2000; Almasan and Ashkenazi, 2003; LeBlanc and Ashkenazi, 2003). Briefly, following engagement of death receptors by their ligand is the recruitment of proteins to the intracellular death domain of the receptor to form a structure known as the death-inducing signaling complex (DISC) (Kischkel et al., 1995). TRAIL DISC resembles that of Fas since the adaptor protein Fas-associated death domain (FADD) and the apoptosis initiator caspase-8 are recruited to DR4 and/or DR5 shortly after addition of the ligand (Bodmer et al., 2000; Kischkel et al., 2000; Sprick et al., 2000). Although initial studies (Kischkel et al., 2000; Sprick et al., 2000) have attributed a central role to caspase-8 in mediating the apoptotic signal of TRAIL, more recent study has demonstrated that apoptosis can be triggered independently through DR4 or DR5 and proteolytic activation of effector caspases by apical caspase-8 or -10 (Kischkel et al., 2001). Similarly to CD95L (Scaffidi et al., 1998), the response to TRAIL is cell type specific and might be characterized by two distinct cell death pathways (reviewed in LeBlanc and Ashkenazi, 2003): in the type I pathway, extrinsic signals lead to the activation of large amounts of caspase-8 and the rapid cleavage of caspase-3 prior to loss of mitochondria trans-membrane potential (ΔΨm); in the type II pathway of apoptosis, intrinsic signals, like DNA damage, lead to the Bcl-2 family member Bax translocation to the mitochondria followed by loss of ΔΨm. This, in turn, induces the release of cytochrome c and its association with Apaf-1 and procaspase-9, which leads to the activation of caspase-9 and the final recruitment of effector caspases (Susin et al., 1999; Green, 2000). Pro-apoptotic members of the Bcl-2 family, such as Bax or its homologue Bak, are counteracted by the anti-apoptotic family members Bcl-2 or Bcl-XL (Bouillet and Strasser, 2002). Other proteins belonging to the Bcl-2 family, such as Bim, Bid, PUMA, and NOXA, contain only one of the four Bcl-2 homology domains (BH3) common to the rest of the family and increase the activity of Bcl-2 family pro-apoptotic members. When low concentrations of caspase-8/-10, insufficient to allow an effective downstream activation of caspase-3, induce cleavage of Bid (tBid), this protein translocates to the mitochondria where it activates Bax and Bak, so that a mechanism for crosstalk between the death receptors and the intrinsic pathway is provided (Li et al., 1998; Bouillet and Strasser, 2002).

Upon binding of TRAIL-R1, -R2, or -R4, TRAIL can also activate the transcriptional factor NF-κB and c-Jun N-terminal kinase (JNK) (Chaudhary et al., 1997; Degli-Esposti et al., 1997b; Schneider et al., 1997b; Muhlenbeck et al., 1998); the activation of NF-κB or Jun-kinase by TRAIL is mediated via TRADD (TNF-R1-associated death domain protein), TRAF2 (TNF receptor-associated factor 2), and RIP (receptor-interacting protein) and occurs independently of caspase-8/-10 activation (Muhlenbeck et al., 1998; Lin et al., 2000; MacFarlane, 2003) (Fig. 1). Importantly, the level of NF-κB activation has been related to resistance of leukemic (Ehrhardt et al., 2003) and neuroblastoma cell lines (Yang and Thiele, 2003) to TRAIL cytotoxicity. These findings are consistent with the pleiotropic activity of NF-κB transcription factors, which are implicated in the control of cell survival and tumorigenesis (Ghosh et al., 1998; Foo and Nolan, 1999; Rayet and Gelinas, 1999). Activation and regulation of Rel/NF-κB proteins are tightly controlled by IκB proteins, which mask the nuclear localization signal (NLS) of NF-κB family members, thereby preventing their nuclear translocation (Siebenlist et al., 1994; Verma et al., 1995; Baeuerle and Baltimore, 1996). In response to many stimuli, such as TNFα, lipopolysaccharide (LPS), or interleukin-1 (IL-1), IκB kinase (IKK) is activated and can phosphorylate IκBs, which, in turn, can be polyubiquitinated and rapidly degraded by the proteasome (Baeuerle and Baltimore, 1996), allowing the release of sequestered NF-κB. Once translocated into the nucleus, NF-κB is able to activate its target genes, which, depending on the physiological circumstances (Barkett and Gilmore, 1999), can mediate cell survival or apoptosis. Among the anti-apoptotic genes up-regulated by NF-κB are included cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1 and c-IAP2), TNFR associated factors 1 and 2 (TRAF1 and TRAF2), cellular FLICE-like inhibitory protein (c-FLIP), and Bcl-XL (Beg and Baltimore, 1996; Liu et al., 1996; Van Antwerp et al., 1996; Wang et al., 1996; Wang et al., 1998). It has been recently documented that the dual function of NF-κB, as an inhibitor or activator of apoptosis, depends on the relative levels of RelA and c-Rel subunits (Chen et al., 2003). Over-expression of RelA or a transcriptional-deficient mutant of c-Rel inhibits TRAIL-induced apoptosis in mouse embryonic fibroblasts, whereas depletion of RelA increases cytokine-induced apoptosis (Chen et al., 2003). NF-κB inactivation has been reported to play a critical role in the sensitization of hepatoma cells to TRAIL-induced apoptosis by interferon-α (Shigeno et al., 2003).

thumbnail image

Figure 1. Schematic representation of TNF-related apoptosis-inducing ligand (TRAIL)-mediated signaling pathways in a hypothetical cell model. Activation of TRAIL receptors can trigger both death and survival pathways, depending on the cell system and environmental conditions. TRAIL-R1 and -R2 can lead to apoptotic cell death by the recruitment of FADD and the following cleavage of caspase-8 and -10. Both death receptors together with the decoy TRAIL-R4 are also involved in the priming of survival genes through the activation of (a) NF-κB and JNK pathways triggered by the engagement of TRAF2 and RIP; (b) PI-3K/Akt and MAPK/ERK1-2 pathways, by means of still unknown mechanisms (highlighted with a question mark). Other mechanisms leading to TRAIL resistance include different caspase or PI-3K physiological inhibitors. The connection between PI-3K/Akt and NOS pathways is also shown.

Download figure to PowerPoint

A number of other reports investigated the intracellular molecules and mechanisms of TRAIL resistance although the complete comprehension of this matter is far from being obtained (Fig. 1). Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer (Chen et al., 2001) and protects HL60 leukemia cells from TRAIL-induced apoptosis by activating NF-κB and up-regulating c-FLIP (Bortul et al., 2003). Akt, also known as protein kinase B (PKB), is a serine/threonine kinase which acts as a transducer of many functions initiated by the growth factor receptors that activate phosphatidylinositol 3-kinase (PI 3-kinase). Experiments performed with a pharmacological inhibitor of the PI 3-kinase/Akt pathway (LY294002) or a dominant-negative Akt (K179M) demonstrated that TRAIL significantly protected primary human endothelial cells (HUVEC) from apoptosis induced by trophic withdrawal via Akt and that inhibition of Akt sensitized HUVEC to TRAIL-induced caspase-dependent apoptosis (Secchiero et al., 2003a). TRAIL also stimulated the ERK1/2, members of the mitogen-activated protein (MAP) kinase family, but not the p38 or the JNK pathways and induced a significant increase in endothelial cell proliferation in an ERK-dependent manner (Secchiero et al., 2003a). Moreover, our group has shown that TRAIL sequentially activates anti-apoptotic (Akt, ERK, and NF-κB) and pro-apoptotic (caspases) pathways in the SK-N-MC neuroblastoma cell model (Milani et al., 2003). A possible interplay between the Akt and caspase pathways has been already described in several cell systems (Cardone et al., 1998; Gibson et al., 2002; Jones et al., 2002; Rokhlin et al., 2002). The picture emerging from these studies is that, when survival signals dominate, Akt impairs the activation of the apical caspases, by directly phosphorylating caspase-9 (Cardone et al., 1998) or by inhibiting the recruitment of procaspase-8/-10 to the death-inducing signaling complex (Jones et al., 2002). On the other hand, when pro-apoptotic signals prevail, apical caspases-8/-10 activate downstream caspases, which cleave and inactivate Akt (Milani et al., 2003) as well as other anti-apoptotic pathways.

Additional cell survival promoting pathways are likely to influence sensitivity to TRAIL-induced apoptosis. The tumor suppressor p53 acts by up-regulating TRAIL-R2 and sensitizing cells to the cytotoxic action of TRAIL (Wu et al., 1997), while protein kinase C (PKC), once activated, is able to inhibit the recruitment of key obligatory death domain-containing adaptor proteins to their respective membrane-associated signaling complexes, thereby modulating TRAIL-induced apoptosis and NF-κB activation (Harper et al., 2003). The involvement of NO (nitric oxide)/NOS (nitric oxide synthase) and COX (cyclooxygenase) pathways has been evidenced in different cell models exposed to TRAIL: primary human endothelial cells (Zauli et al., 2003), HL60 cells, normal human CD34+ cells and freshly isolated peripheral blood (PB) CD14+ monocytes (Secchiero et al., 2002). Interestingly, whereas no cytotoxic effects were observed in primary normal cells, in myeloid leukemia cell lines TRAIL-mediated cytotoxicity was significantly enhanced by the association with NO donors, such as sodium nitroprusside (SNP), which, when used alone, displayed only minimal cytotoxicity on leukemic cells (Richardson et al., 1995; Shami et al., 1995; Secchiero et al., 2002).

Finally, beside the molecules activated by TRAIL inside the cell, it is worth outlining that TRAIL can itself transduce a reverse signal outside the cell (Chou et al., 2001) or can be induced itself at gene level by a number of molecules. Among these molecules, the most important are IFNs, which play an essential role in host defense through their anti-viral and anti-tumor effects, but which can also lead to apoptotic death in various cancer cell lines (reviewed in Chawla-Sarkar et al., 2003). The latter effect would be mediated by transcriptional induction of TRAIL gene following recruitment at receptor level of the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway (Stark et al., 1998).

Biological effects and physiological roles

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  7. CONCLUSION
  8. Acknowledgements
  9. LITERATURE CITED

Since a few years ago, the known biological activity of TRAIL was far limited to induce apoptosis in various cell lines, including some of hematopoietic origin (Snell et al., 1997; Clodi et al., 2000). In more recent years, new regulatory, pro-survival and proliferation effects are being attributed to this cytokine (Chu et al., 1997; Secchiero et al., 2002, 2003a; Zauli et al., 2003) and, what was more unexpected, this was not restricted to normal primary cells, but extended to neoplastic cell lines of leukemic and non-leukemic origin (Ehrhardt et al., 2003).

TRAIL has been shown to induce apoptosis in a number of tumor cell lines as well as in some primary tumors whereas cells from most normal tissues are highly resistant to TRAIL-induced apoptosis (Table 1). A number of drugs have been used in combination with TRAIL to increase the induction of apoptosis both in cell lines (Liu et al., 2003; Siervo-Sassi et al., 2003) and in cells freshly isolated from myeloma patients (Liu et al., 2003). Although a role for TRAIL in physiologic conditions has not been clearly envisioned yet, TRAIL shows inhibitory effects on normal immature erythroblasts (De Maria et al., 1999; Zamai et al., 2000; Secchiero et al., 2004), T lymphocytes (Marsters et al., 1996; Song et al., 2000), and hepatocytes (Jo et al., 2000). To explore whether TRAIL might play a role in the homeostatic control of hematopoiesis, freshly isolated adult PB CD34+ hematopoietic progenitors as well as erythroid (glycophorin A+), megakaryocytic (CD61+), granulocytic (CD15+), and monocytic (CD14+) precursor cells generated in vitro in liquid suspensions and semisolid cultures were employed (Zamai et al., 2000). Pre-exposure to TRAIL significantly decreased the number and size of erythroid colonies in semisolid assays without influencing the survival of cells differentiating along the megakaryocytic, granulocytic, or monocytic lineages. In spite of this negative regulation of erythropoiesis, TRAIL acts as a positive regulator of myeloid differentiation, since it is able to increase the number of mature monocytes and macrophages when added to liquid cultures of primary normal CD34+ cells induced with SCF and GM-CSF in the absence of cytotoxic effects (Secchiero et al., 2002). Instead, this maturation effect is paralleled by a rapid cytotoxicity in malignant HL60 cell line (Secchiero et al., 2002, 2003b), disclosing therapeutic implications for the treatment of acute myeloid leukemia.

TRAIL/Apo2L is expressed on different cells of the immune system including CD4+ T cells, NK cells, macrophages and dendritic cells and plays a role in NK cell-mediated tumor surveillance (Kayagaki et al., 1999a,b; Kaplan et al., 2000; Wallin et al., 2003) and in preventing autoimmunity, as recently displayed in mouse models (Song et al., 2000). On the other hand, the up-regulation of TRAIL expression was related to an enhanced lymphocyte proliferation and IFN-γ production in mouse models following TCR activation (Chou et al., 2001). This finding represents another example of reverse signal transduction already described in the activation of the immune system by other members of the TNF super-family (Wiley et al., 1996; Lens et al., 1999; Suzuki and Fink, 2000). Interestingly, in virus-induced diseases, including AIDS, an increased expression of TRAIL in infected cells is one of the mechanisms responsible for virus-induced apoptosis (Sedger et al., 1999; Clarke et al., 2000; Miura et al., 2001).

Finally, a novel role of this cytokine is emerging in endothelial cell physiology regulation (Secchiero et al., 2003a; Zauli et al., 2003). In fact, in primary human endothelial cells TRAIL is able to promote either survival or proliferation as well as cell migration and cytoskeleton reorganization, without inducing NF-κB activation and inflammatory markers.

Clinical perspectives and therapeutic use

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  7. CONCLUSION
  8. Acknowledgements
  9. LITERATURE CITED

It has been shown that TRAIL induces growth arrest and apoptosis in cancer cells independently of p53 wild-type function (Levine, 1997), Bcl-2 and Bcl-XL (Walczak and Krammer, 2000) and MDR gene expression (Snell et al., 1997). Thus, TRAIL may offer an alternative or complementary approach to conventional anticancer therapy. Unlike other members of the TNF super-family, such as CD95L and TNFα, that are precluded from use in systemic anticancer therapy due to their severe toxic side effects (Tartaglia and Goeddel, 1992; Nagata, 1997), TRAIL is effective in selectively killing both in vitro and in vivo a vast array of tumor cells from lung, breast, kidney, colon, prostate, thyroid, and skin cancers (Sheikh et al., 1998; Gliniak and Le, 1999; Keane et al., 1999; Sedger et al., 1999; Walczak et al., 1999; Ahmad and Shi, 2000; Yu et al., 2000), without causing significant organ toxicity and inflammation in vivo. Although it is not established whether TRAIL causes liver toxicity in humans (Jo et al., 2000; Lawrence et al., 2001), pre-clinical studies are promising. Recombinant human TRAIL protein systematically injected in mice and non-human primates promotes potent apoptosis-inducing activity against tumor cells (Ashkenazi et al., 1999; Walczak et al., 1999). Moreover, newly developed anti-TRAIL-R2 antibodies exhibit strong anti-tumor activity both in vitro and in vivo without displaying hepatocyte cytotoxicity (Ichikawa et al., 2001). Therefore, TRAIL is a strong candidate for an effective but tolerable treatment of solid cancers, either used alone or in combination with radio/chemotherapy. In this respect, it has been proposed that TRAIL synergistically cooperates with: (i) chemotherapeutic drugs, such as etoposide, campthotecin-11, doxorubicin, 5-fluorouracil, taxol (Keane et al., 1999; Gliniak and Lee, 1999; Kim et al., 2000; Nagane et al., 2000; Gibson et al., 2002); and (ii) ionizing radiation (Chinnaiyan et al., 2000; Zhou et al., 2000), causing substantial regression or complete ablation of solid (colon and mammary) cancers in animal models. Besides acting as a tumor suppressor in vivo in primary tumors, TRAIL could play a substantial role in suppressing tumor metastasis. In fact, it has been observed that this cytokine may partially limit the formation of hepatic metastases of a variety of mouse tumors (Seki et al., 2003). It has also been shown that TRAIL exerts a variable cytotoxic activity on hematological malignancies (Snell et al., 1997), and we and other authors have demonstrated that TRAIL-mediated cytotoxicity is increased by ionizing radiation and chemotherapeutic drugs in both myeloid and erythroid leukemic cell lines as well as in T lymphoma cell lines (Gong and Almasan, 2000; Wen et al., 2000; Di Pietro et al., 2001). Day by day, an increasing number of drugs warrant further investigation as potential new strategies for the treatment of human glioma (Hermisson and Weller, 2003), lung cancer (Frese et al., 2003), myeloma (Liu et al., 2003), or acute myelogenous leukemia (AML) in combination with recombinant soluble TRAIL (Suh et al., 2003). In addition, TRAIL has been recently proposed to be used as an ex vivo purging agent for autologous transplantation in hematological malignancies (Lee et al., 2003).

The scenario emerging from all these studies is that the therapeutic use of TRAIL as an inducer of tumor specific cell death can be considered as an useful strategy to overcome resistance of cancer cells to conventional chemotherapeutic agents (Bhojani et al., 2003). But some concerns are inevitable in light of a very recent report showing that TRAIL, unlike other death inducing ligands, such as TNFα and CD95L, is able to induce cancer cell proliferation in a wide range of neoplastic diseases (Ehrhardt et al., 2003). Given the promising therapeutic potential of TRAIL as a novel anticancer drug, TRAIL-mediated survival or proliferation of target cells may restrict its use to apoptosis-sensitive tumors and may represent a potential risk for patients with TRAIL apoptosis-resistant tumor cells as it might increase tumor growth. Further studies based on in vivo animal models of TRAIL apoptosis-resistant tumors are necessary to elaborate the clinical relevance of TRAIL-mediated survival and proliferation of TRAIL apoptosis-resistant tumors.

Finally, a special mention deserves the new perspective to use TRAIL in association to immune therapy both in cancer therapy (Suh et al., 2003) and as a potential response marker for IFNβ treatment in multiple sclerosis (Wandinger et al., 2003).

CONCLUSION

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  7. CONCLUSION
  8. Acknowledgements
  9. LITERATURE CITED

This review was focused to present new emerging anti-apoptotic roles of TRAIL in physiologic and patho-physiologic conditions. We are aware that few data are available up to now concerning normal cells and their different sensitivity to this ligand but we hope to have stimulated discussion and to have given a little contribution to the understanding of this intriguing ligand-receptor system in view of a possible use of TRAIL as a “protective” agent in particular body compartments and conditions.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  7. CONCLUSION
  8. Acknowledgements
  9. LITERATURE CITED

The authors thank Miss Luciana Caravatta for artwork and bibliographic research. This study was partially supported with 2001 MIUR COFIN funds “Studio dei meccanismi sottostanti la citotossicità di TRAIL in neoplasie ematologiche: basi per una terapia combinata.”

LITERATURE CITED

  1. Top of page
  2. Abstract
  3. Molecular structure and receptors
  4. Signaling pathways and genes activated
  5. Biological effects and physiological roles
  6. Clinical perspectives and therapeutic use
  7. CONCLUSION
  8. Acknowledgements
  9. LITERATURE CITED
  • Almasan A, Ashkenazi A. 2003. Apo2L/TRAIL: Apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev 14: 337348.
  • Ashkenazi A, Dixit VM. 1999. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 11: 255260.
  • Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z, Schwall RH. 1999. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 104: 155162.
  • Baeuerle PA, Baltimore D. 1996. NF-kappa B: Ten years after. Cell 87(1): 1320.
  • Baker SJ, Reddy EP. 1996. Transducers of life and death: TNF receptor superfamily and associated proteins. Oncogene 12: 19.
  • Barkett M, Gilmore TD. 1999. Control of apoptosis by Rel/NF-κB transcription factors. Oncogene 18: 69106924.
  • Beg AA, Baltimore D. 1996. An essential role for NF-κB in preventing TNFα-induced cell death. Science 274: 782784.
  • Bhojani MS, Rossu BD, Rehemtulla A. 2003. TRAIL and anti-tumor responses. Cancer Biol Ther 2(4 Suppl 1): S71S78.
  • Bodmer JL, Holler N, Reynard S, Vinciguerra P, Schneider P, Juo P, Blenis J, Tschopp J. 2000. TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol 2: 241243.
  • Bortul R, Tazzari PL, Cappellini A, Tabellini G, Billi AM, Bareggi R, Manzoli L, Cocco L, Martelli AM. 2003. Constitutively active Akt1 protects HL60 leukemia cells from TRAIL-induced apoptosis through a mechanism involving NF-kappaB activation and cFLIP(L) up-regulation. Leukemia 17: 379389.
  • Bouillet P, Strasser A. 2002. BH3-only proteins-evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death. J Cell Sci 115: 15671574.
  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC. 1998. Regulation of cell death protease caspase-9 by phosphorylation. Science 282: 13181321.
  • Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L. 1997. Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-κB pathway. Immunity 7: 821830.
  • Chawla-Sarkar M, Lindner DJ, Liu Y-F, Williams BR, Sen GC, Silverman RH, Borden EC. 2003. Apoptosis and interferons: Role of interferon-stimulated genes as mediators of apoptosis. Apoptosis 8(3): 237249.
  • Chen X, Thakkar H, Tyan F, Gim S, Robinson H, Lee C, Pandey SK, Nwokorie C, Onwudiwe N, Srivastava RK. 2001. Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene 20: 60736083.
  • Chen X, Kandasamy K, Srivastava RK. 2003. Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B in tumor necrosis factor-related apoptosis-inducing ligand signaling. Cancer Res 63: 10591066.
  • Chou A-H, Tsai H-F, Lin S-L, Hsu P-I, Hsu P-N. 2001. Enhanced proliferation and increased IFN-γ production in T cells by signal transduced through TNF-related apoptosis-inducing ligand. J Immunol 167: 13471352.
  • Chu CH, McKinsey T, Liu L, Gentry J, Malim M, Ballard DW. 1997. Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-κB control. Proc Natl Acad Sci USA 94: 1005710062.
  • Clarke P, Meintzer SM, Gibson S, Widmann C, Garrington TP, Johnson GL, Tyler KL. 2000. Reovirus-induced apoptosis is mediated by TRAIL. J Virol 74: 81358139.
  • Clodi K, Wimmer D, Li Y, Goodwin R, Jaeger U, Mann G, Gadner H, Younes A. 2000. Expression of tumor necrosis factor (TNF)-related apoptosis.inducing ligand (TRAIL) receptors and sensitivity to TRAIL-induced apoptosis in primary B-cell acute lymphoblastic leukaemia cells. Br J Haematol 111: 580586.
  • De Maria R, Zeuner A, Eramo A, Domenichelli C, Bonci D, Grignani F, Srinivasula SM, Alnemri ES, Testa U, Peschle C. 1999. Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature 401: 489493.
  • Degli-Esposti MA, Smolak PJ, Walczak H, Waugh J, Huang CP, DuBose RF, Goodwin RG, Smith CA. 1997a. Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family. J Exp Med 186: 11651170.
  • Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG. 1997b. The novel receptor TRAIL-R4 induces NF-κB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 7: 813820.
  • Di Pietro R, Secchiero P, Rana R, Gibellini D, Visani G, Bemis K, Zamai L, Miscia S, Zauli G. 2001. Ionizing radiation sensitizes erythroleukemic cells but not normal erythroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity by selective up-regulation of TRAIL-R1. Blood 97(9): 25962603.
  • Ehrhardt H, Fulda S, Schmid I, Hiscott J, Debatin K-M, Jeremias I. 2003. TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-κB. Oncogene 22: 38423852.
  • Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR. 1998. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 273: 1436314367.
  • Foo S, Nolan G. 1999. NF-κB to the rescue. Trends Genet 15: 229235.
  • Frese S, Pirnia F, Miescher D, Krajewski S, Borner MM, Reed JC, Schmid RA. 2003. PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2. Oncogene 22: 54275435.
  • Ghosh S, May M, Kopp E. 1998. NF-κB, and Rel proteins evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16: 225260.
  • Gibson EM, Henson ES, Haney N, Villanueva J, Gibson SB. 2002. Epidermal growth factor protects epithelial-derived cells from tumor necrosis factor-related apoptosis-inducing ligand induced apoptosis by inhibiting cytochrome c release. Cancer Res 62: 488496.
  • Gong B, Almasan A. 2000. Genomic organization and transcriptional regulation of the human Apo2L/TRAIL gene. Biochem Biophys Res Commun 278: 747752.
  • Green D. 2000. Apoptotic pathways: Paper wraps stone blunts scissors. Cell 102: 14.
  • Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ. 1998. Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 161: 28332840.
  • Gruss HJ, Dower SK. 1995. Tumor necrosis factor ligand superfamily: Involvement in the pathology of malignant lymphomas. Blood 85: 33783404.
  • Harper N, Hughes MA, Farrow SN, Cohen GM, MacFarlane M. 2003. Protein kinase C modulates TRAIL-induced apoptosis by targeting the apical events of death receptor signaling. J Biol Chem 278(45): 4433844347.
  • Hermisson M, Weller M. 2003. NF-kappaB-independent actions of sulfasalazine dissociate the CD95L- and Apo2L/TRAIL-dependent death signaling pathways in human malignant glioma cells. Cell Death Differ 10: 10781089.
  • Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connel M, Kelley RF, Ashkenazi A, de Vos AM. 1999. Triggering cell death: The crystal structure of Apo2L/TRAIL in a complex with death receptor5. Mol Cell 4: 563571.
  • Ichikawa K, Liu W, Zhao L, Wang Z, Liu D, Ohtsuka T, Zhang H, Mountz JD, Koopman WJ, Kimberly RP, Zhou T. 2001. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med 7: 954960.
  • Jo M, Kim TH, Seol DW, Esplen JE, Dorko K, Billiar TR, Strom SC. 2000. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat Med 6: 556564.
  • Jones RG, Elford AR, Parsons MJ, Wu L, Krawczyk CM, Yeh WC, Hakem R, Rottapel R, Woodgett JR, Ohashi PS. 2002. CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly. J Exp Med 196: 335348.
  • Kaplan MJ, Ray D, Mo RR, Yung RL, Richardson BC. 2000. TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell-killing of antigen-presenting macrophages. J Immunol 164: 28972904.
  • Kayagaki N, Yamaguchi N, Nakayama M, Kawasaki A, Akiba H, Okumura K, Yagita H. 1999a. Involvement of TNF-related apoptosis-inducing ligand in human CD4+ T cell-mediated cytotoxicity. J Immunol 162: 26392647.
  • Kayagaki N, Yamaguchi N, Nakayama M, Takeda K, Akiba H, Tsutsui H, Okamura H, Nakanishi K, Okumura K, Yagita H. 1999b. Expression and function of TNF-related apoptosis-inducing ligand on murine activated NK cells. J Immunol 163: 19061913.
  • Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME. 1995. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14: 55795588.
  • Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A. 2000. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12: 611620.
  • Kischkel FC, Lawrence DA, Tinel A, Virmani A, Schow P, Gazdar A, Blenis J, Arnott D, Ashkenazi A. 2001. Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. J Biol Chem 276: 4663946646.
  • Lawrence D, Sdhahroth Z, Marsters S, Achilles K, Shih D, Mounho B, Hillan K, Totpal K, DeForge L, Schow P, Hooley J, Sherwood S, Pai R, Leung S, Khan L, Gliniak B, Bussiere J, Smith CA, Strom SS, Kelley S, Fox JA, Thomas D, Ashkenazi A. 2001. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 7: 383385.
  • LeBlanc HN, Ashkenazi A. 2003. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ 10: 6675.
  • Lee NS, Cheong HJ, Kim SJ, Kim SE, Kim CK, Lee KT, Park SK, Baick SH, Hong DS, Park HS, Won JH. 2003. Ex vivo purging of leukemia cells using tumor-necrosis-factor-related apoptosis-inducing ligand in hematopoietic stem cell transplantation. Leukemia 17(7): 13751383.
  • Lens SM, Drillenburg P, den Drijver BF, van Schijndel G, Pals ST, van Lier RA, van Oers HM. 1999. Aberrant expression and reverse signaling of CD70 on malignant B cells. Br J Hematol 106: 491503.
  • Leverkus M, Neumann M, Mengling T, Rauch C, Broecker E-B, Krammer PH, Walczak H. 2000. Regulation of TRAIL sensitivity in primary and transformed human keratinocytes. Cancer Res 60: 553559.
  • Li H, Zhu H, Xu C-J, Yuan J. 1998. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway to apoptosis. Cell 94: 491501.
  • Lin Y, Devin A, Cook A, Keane MM, Kelliher M, Lipkowitz S, Liu ZG. 2000. The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IkappaB kinase and c-Jun N-terminal kinase. Mol Cell Biol 20: 66386645.
  • Liu ZG, Hsu H, Goeddel DV, Karin M. 1996. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell 87: 565576.
  • Liu Q, Hilsenbeck S, Gazitt Y. 2003. Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. Blood 101: 40784087.
  • MacFarlane M. 2003. TRAIL-induced signaling and apoptosis. Toxicol Lett 139: 8997.
  • Mariani SM, Krammer PH. 1998. Differential regulation of TRAIL and CD95 ligand in transformed cells of the T and B lymphocyte lineage. Eur J Immunol 28: 973982.
  • Marsters S, Pitti RM, Donahue CJ, Ruppert S, Bauer KD, Ashkenazi A. 1996. Activation of apoptosis by Apo-2 ligand is independent of FADD but blocked by CrmA. Curr Biol 6: 750752.
  • Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, Yuan J, Gurney A, Goddard AD, Godowski P, Ashkenazi A. 1997. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol 7: 10031006.
  • Milani D, Zauli G, Rimondi E, Celeghini C, Marmiroli S, Narducci P, Capitani S, Secchiero P. 2003. Tumour necrosis factor-related apoptosis-inducing ligand sequentially activates pro-survival and pro-apoptotic pathways in SK-N-MC neuronal cells. J Neurochem 86: 126135.
  • Miura Y, Misawa N, Maeda N, Inagaki Y, Tanaka Y, Ito M, Kayagaki N, Yamamoto N, Yagita H, Mizusawa H, Koyanagi Y. 2001. Critical contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to apoptosis of human CD4(+) T cells in HIV-1-infected Hu-PBL-NOD-SCID mice. J Exp Med 193: 651660.
  • Muhlenbeck F, Haas E, Schwenzer R, Schubert G, Grell M, Smith C, Scheurich P, Waiant H. 1998. TRAIL/Apo2L activates c-Jun NH2-terminal kinase (JNK) via caspase-dependent and caspase-independent pathways. J Biol Chem 273: 3309133098.
  • Nagata S. 1997. Apoptosis by death factor. Cell 88: 355365.
  • Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM. 1997a. The receptor for the cytotoxic ligand TRAIL. Science 276: 111113.
  • Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. 1997b. An antagonist decoy receptor and a new death domain-containing receptor for TRAIL. Science 277: 815818.
  • Pan G, Ni J, Yu G, Wei YF, Dixit VM. 1998. TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signaling. FEBS Lett 424: 4145.
  • Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. 1996. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 271: 1268712690.
  • Rayet B, Gelinas C. 1999. Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18: 69386947.
  • Richardson DR, Neumannova V, Nagy E, Ponka P. 1995. The effect of redox-related species of nitrogen monoxide on transferring and iron uptake and cellular proliferation of erythroleukemia (K562) cells. Blood 86: 32113219.
  • Rokhlin OW, Guseva NV, Tagiyev AF, Glover RA, Cohen MB. 2002. Caspase-8 activation is necessary but not sufficient for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in the prostatic carcinoma cell line LNCaP. Prostate 52: 111.
  • Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME. 1998. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17: 16751687.
  • Schneider P, Bodmer JL, Thome M, Hofmann K, Holler N, Tschopp J. 1997a. Characterization of two receptors for TRAIL. FEBS Lett 416: 329334.
  • Schneider P, Thome M, Burns K, Bodmer JL, Hofman K, Kataoka T, Holler N, Tschopp J. 1997b. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-κB. Immunity 7: 831836.
  • Screaton GR, Mongkolsapaya J, Xu XN, Cowper AE, McMichael AJ, Bell JI. 1997. TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL. Curr Biol 7: 693696.
  • Secchiero P, Gonelli A, Mirandola P, Melloni E, Zamai L, Celeghini C, Milani D, Zauli G. 2002. Tumor necrosis factor-related apoptosis-inducing ligand induces monocytic maturation of leukemic and normal myeloid precursors through a caspase-dependent pathway. Blood 100: 24212429.
  • Secchiero P, Gonelli A, Carnevale E, Milani D, Pandolfi A, Zella D, Zauli G. 2003a. TRAIL promotes the survival and proliferation of primary human vascular endothelial cells by activating the Akt and ERK pathways. Circulation 107: 22502256.
  • Secchiero P, Milani D, Gonelli A, Melloni E, Campioni D, Gibellini D, Capitani S, Zauli G. 2003b. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF-alpha promote the NF-kappaB-dependent maturation of normal and leukemic myeloid cells. J Leukoc Biol 74: 223232.
  • Secchiero P, Melloni E, Heikinheimo M, Mannisto S, Di Pietro R, Iacone A, Zauli G. 2004. TRAIL regulates normal erythroid maturation through an ERK-dependent pathway. Blood 103(2): 517522.
  • Sedger LM, Shows DM, Blanton RA, Peschon JJ, Goodwin RG, Cosman D, Wiley SR. 1999. IFN-gamma mediates a novel antiviral activity through dynamic modulation of TRAIL and TRAIL receptor expression. J Immunol 163: 920926.
  • Seki N, Hayakawa Y, Brooks AD, Wine J, Wiltrout RH, Yagita H, Tanner JE, Smyth MJ, Sayers TJ. 2003. Tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis is an important endogenous mechanism for resistance to liver metastases in murine renal cancer. Cancer Res 63: 207213.
  • Shami PJ, Moore JO, Gockerman JP, Hathorn JW, Misukonis MA, Weinberg JB. 1995. Nitric oxide modulation of the growth and differentiation of freshly isolated acute non-lymphocytic leukemia cells. Leuk Res 9: 527533.
  • Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A. 1997. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277: 818821.
  • Shigeno M, Nakao K, Ichikawa T, Suzuki K, Kawakami A, Abiru S, Miyazoe S, Nakagawa Y, Ishikawa H, Hamasaki K, Nakata K, Ishii N, Eguchi K. 2003. Interferon-alpha sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-kappaB inactivation. Oncogene 22: 16531662.
  • Siebenlist U, Franzoso G, Brown K. 1994. Structure, regulation and function of NF-κB. Annu Rev Cell Biol 19: 405455.
  • Siervo-Sassi RR, Marrangoni AM, Feng X, Naoumova N, Winans M, Edwards RP, Lokshin A. 2003. Physiological and molecular effects of Apo2L/TRAIL and cisplatin in ovarian carcinoma cell lines. Cancer Lett 190: 6172.
  • Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ, et al. 1997. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 89: 309319.
  • Smith CA, Farrah T, Goodwin RG. 1994. The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death. Cell 76: 959962.
  • Snell V, Clodi K, Zhao S, Goodwin R, Thomas EK, Morris SW, Kadin ME, Cabanillas F, Andreeff M, Younes A. 1997. Activity of TNF-related apoptosis-inducing ligand (TRAIL) in haematological malignancies. Br J Haematol 99: 618624.
  • Song K, Chen Y, Goke R, Wilmen A, Seidel C, Goke A, Hilliard B, Chen Y. 2000. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J Exp Med 191: 10951104.
  • Sprick MR, Weigand MA, Rieser E, Rausch CT, Juo P, Blenis J, Krammer PH, Walczak H. 2000. FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12: 599609.
  • Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. 1998. How cells respond to interferons. Annu Rev Biochem 67: 227264.
  • Suh WS, Kim YS, Schimmer AD, Kitada S, Minden M, Andreeff M, Suh N, Sporn M, Reed JC. 2003. Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL. Leukemia 17(11): 21222129.
  • Susin SA, Lorenzo HK, Zamzami N, Marzo I, Brenner C, Larochette N, Prevost MC, Alzari PM, Kroemer G. 1999. Mitochondrial release of caspase-2 and -9 during the apoptotic process. J Exp Med 189: 381393.
  • Suzuki I, Fink PJ. 2000. The dual functions of Fas ligand in the regulation of peripheral CD8+ and CD4+ T cells. Proc Natl Acad Sci USA 97: 17071712.
  • Tartaglia LA, Goeddel DV. 1992. Two TNF receptors. Immunol Today 13: 151153.
  • Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM. 1996. Suppression of TNF-alpha-induced apoptosis by NF-κB. Science 274: 787789.
  • Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. 1995. Rel/NF-kappa B/I kappa B family: Intimate tales of association and dissociation. Genes Dev 9(22): 27232735.
  • Walczak H, Krammer PH. 2000. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) Apoptosis Systems. Exp Cell Res 256: 5866.
  • Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT. 1997. TRAIL-R2: A novel apoptosis-mediating receptor for TRAIL. EMBO J 16: 53865397.
  • Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC, Lynch DH. 1999. Tumoricidal activity of tumor-necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 5: 157163.
  • Wallin RP, Screpanti V, Michaelsson J, Grandien A, Ljunggren HG. 2003. Regulation of perforin-independent NK cell-mediated cytotoxicity. Eur J Immunol 33(10): 27272735.
  • Wang CY, Mayo MW, Baldwin AS, Jr. 1996. TNF- and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-κB. Science 274: 784787.
  • Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS, Jr. 1998. NF-κB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 274: 782784.
  • Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Davis-Smith T, Rauch C, Smith CA, Goodwin RG. 1995. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3: 673682.
  • Wiley SR, Goodwin RG, Smith CA. 1996. Reverse signaling via CD30 ligand. J Immunol 157: 36353639.
  • Wu GS, Burns TF, McDonald ER III, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G, el-Deiry WS. 1997. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 17: 141143.
  • Yang X, Thiele CJ. 2003. Targeting the tumor necrosis factor-related apoptosis-inducing ligand path in neuroblastoma. Cancer Lett 197(1-2): 137143.
  • Zamai L, Secchiero P, Pierpaoli S, Bassini A, Papa S, Alnemri ES, Guidotti L, Vitale M, Zauli G. 2000. TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropopiesis. Blood 95: 37163724.
  • Zauli G, Pandolfi A, Gonelli A, Di Pietro R, Guarnieri S, Ciabattoni G, Rana R, Vitale M, Secchiero P. 2003. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sequentially upregulates nitric oxide and prostanoid production in primary human endothelial cells. Circ Res 92: 732740.
  • Zhang XD, Franco A, Myers K, Gray C, Nguyen T, Hersy P. 1999. Relation of TNF-related apoptosis inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 59: 27472753.