28 Modulation of TRAIL Signaling for Cancer Therapy
Simone Fulda, MD, and Klaus-Michael Debatin, MD
Summary
Apoptosis, the cell’s intrinsic death program, is a key regulator of tissue homeostasis, and an imbalance between cell death and proliferation may result in tumor formation. Also, killing of cancer cells by cytotoxic therapies such as chemotherapy, -irradiation, or ligation of death receptors is predominantly mediated by triggering apoptosis in target cells. Tumor necrosis factor (TNF)-related apoptosis- inducing ligand (TRAIL) is a member of the TNF superfamily that induces apoptosis upon binding to its receptors. TRAIL is of special interest for cancer therapy, as TRAIL has been shown to predominantly kill cancer cells, while sparing normal cells. Importantly, combined treatment with TRAIL together with chemotherapy or
-irradiation synergized to achieve antitumor activity in tumor cell lines and also in tumor models in vivo. However, failure to undergo apoptosis in response to TRAIL treatment may result in tumor resistance. Understanding the molecular events that regulate TRAIL-induced apoptosis and their deregulation in resistant forms of cancer may provide new opportunities for cancer therapy. Thus, novel strategies targeting tumor cell resistance will be based on further insights into the molecular mechanisms of cell death, for example, triggered by TRAIL.
Key Words: Apoptosis; TRAIL; drugs; cancer therapy.
1. INTRODUCTION
Apoptosis, a distinct, intrinsic cell death program, occurs in various physio- logical and pathological situations and has an important regulatory function in tissue homeostasis and immune regulation (1,2). Apoptosis is characterized by typical morphological and biochemical hallmarks including cell shrinkage, nuclear DNA fragmentation, and membrane blebbing (1). Various stimuli can trigger an apoptosis response, for example, withdrawal of growth factors, or stimulation of cell-surface receptors (1). Also, killing of tumor cells by diverse cytotoxic strategies such as
From: Cancer Drug Discovery and Development Apoptosis, Senescence, and Cancer
Edited by: D. A. Gewirtz, S. E. Holt and S. Grant © Humana Press Inc., Totowa, NJ 579
anticancer drugs, -irradiation, or immunotherapy has been shown to involve induction of apoptosis in target cells (3–5). In addition, T cells or NK cells may release cytotoxic compounds such as granzyme B, which can directly initiate apoptosis effector pathways inside the cell (1). Proteolytic enzymes called caspases are important effector molecules of different forms of cell death (6). Apoptosis pathways are tightly controlled by a number of inhibitory and promoting factors (7). The antiapoptotic mechanisms regulating apoptotic cell death have also been implicated in conferring drug resistance to tumor cells (5). Importantly, combinations of anticancer agents together with death- inducing ligands have been shown to synergize in triggering apoptosis in cancer cells and may even overcome some forms of drug resistance (8). Further insights into the mechanisms controlling tumor cell death in response to death receptor ligation will provide a molecular basis for novel strategies targeting death pathways in apoptosis- resistant forms of cancer.
2. THE CORE APOPTOTIC MACHINERY
In most cases, anticancer therapies eventually result in the activation of caspases, a family of cysteine proteases that act as common death effector molecules in various forms of cell death (6). Caspases are synthesized as inactive proforms, and upon activation, they cleave next to aspartate residues. The fact that caspases can activate each other by cleavage at identical sequences results in the amplification of caspase activity through a protease cascade. Caspases cleave a number of different substrates in the cytoplasm or nucleus leading to many of the morphologic features of apoptotic cell death (1). For example, polynucleosomal DNA fragmentation is mediated by cleavage of inhibitor of caspase-activated DNase (ICAD), the inhibitor of the endonuclease CAD that cleaves DNA into the characteristic oligomeric fragments (9). Likewise, proteolysis of several cytoskeletal proteins such as actin or fodrin leads to loss of overall cell shape, whereas degradation of lamin results in nuclear shrinking (1).
Activation of caspases can be initiated from different angles, for example, at the plasma membrane upon ligation of death receptor (receptor pathway) or at the mitochondria (mitochondrial pathway) (8). Stimulation of death receptors of the tumor necrosis factor (TNF) receptor superfamily such as CD95 (APO-1/Fas) or TNF-related apoptosis-inducing ligand (TRAIL) receptors results in the activation of the initiator caspase-8, which can propagate the apoptosis signal by direct cleavage of downstream effector caspases such as caspase-3 (10). The mitochondrial pathway is initiated by the release of apoptogenic factors such as cytochrome c, apoptosis-inducing factor (AIF), Smac/Diablo, Omi/HtrA2, endonuclease G, caspase-2, or caspase-9 from the mitochon- drial intermembrane space (11). The release of cytochrome c into the cytosol triggers caspase-3 activation through the formation of the cytochrome c/Apaf-1/caspase-9- containing apoptosome complex (12). Smac/Diablo and Omi/HtrA2 promote caspase activation through neutralizing the inhibitory effects to inhibitor of apoptosis proteins (IAPs) (11).
Links between the receptor and the mitochondrial pathway exist at different levels.
Upon death, receptor triggering activation of caspase-8 may result in cleavage of Bid, a Bcl-2 family protein with a BH3 domain only, which in turn translocates to mitochondria to release cytochrome c thereby initiating a mitochondrial amplification loop (13). In addition, cleavage of caspase-6 downstream of mitochondria may feed back to the receptor pathway by cleaving caspase-8 (14).
3. TRAIL AND ITS RECEPTORS
TRAIL/Apo-2L was identified in 1995 based on its sequence homology to other members of the TNF superfamily (15,16). TRAIL is a type II transmembrane protein, the extracellular domain of which can be proteolytically cleaved from the cell surface.
TRAIL is constitutively expressed in a wide range of tissues. Comprising five different receptors, the complexity of the TRAIL receptor system is unprecedented. TRAIL-R1 and TRAIL-R2, the two agonistic TRAIL receptors, contain a conserved cytoplasmic death domain motif, which enables them to engage the cell’s apoptotic machinery upon ligand binding (17–21). TRAIL-R3 to TRAIL-R5 are antagonistic decoy receptors, which bind TRAIL, but do not transmit a death signal (22–26). TRAIL-R3 is a glycosyl- phosphatidylinositol (GPI)-anchored cell-surface protein, which lacks a cytoplasmic tail, whereas TRAIL-R4 harbors a substantially truncated cytoplasmic death domain.
In addition to these four membrane-associated receptors, osteoprotegerin is a soluble decoy receptor, which is involved in the regulation of osteoclastogenesis (27).
Similar to CD95L, TRAIL rapidly triggers apoptosis in many tumor cells (28–30).
The TRAIL ligand and its receptors are of special interest for cancer therapy, as TRAIL has been shown to predominantly kill cancer cells while sparing normal cells.
The underlying mechanisms for the differential sensitivity of malignant versus non- malignant cells for TRAIL have not exactly been defined. One possible mechanism of protection of normal tissues is thought to be based on the set of antagonistic decoy receptors, which compete with TRAIL-R1 and TRAIL-R2 for binding to TRAIL (31).
However, screening of various tumor cell types and normal cells did not reveal a consistent association between TRAIL sensitivity and TRAIL receptor expression.
Therefore, susceptibility for TRAIL-induced cytotoxicity has been suggested to be regulated intracellularly by distinct patterns of pro- and antiapoptotic molecules.
4. TRAIL SIGNALING
Similar to the CD95 system, ligation of the agonistic TRAIL receptors, TRAIL-R1 and TRAIL-R2, by TRAIL or agonistic antibodies results in receptor trimerization and clustering of the receptors’ death domains (28,30,32–34). This leads to recruitment of adaptor molecules such as FADD through homophilic interaction mediated by the death domain. FADD in turn recruits caspase-8 to the activated TRAIL receptor complex. Oligomerization of caspase-8 at the activated TRAIL receptor complex drives its activation through self-cleavage. Caspase-8 then activates downstream effector caspases such as caspase-3. Also, activated caspase-8 can cleave Bid, which then translocates to mitochondria to induce cytochrome c release. In addition to caspase-8, caspase-10 is recruited to the TRAIL DISC (33). However, the importance of caspase- 10 in the TRAIL DISC for apoptosis induction has been controversially discussed (35,36).
5. DEFECTIVE TRAIL SIGNALING IN CANCERS
Signaling by agonistic TRAIL receptors is regulated at various levels along the signaling pathway. Importantly, cancer cells have evolved numerous ways to evade induction of apoptosis triggered by the death ligand TRAIL, resulting in TRAIL resistance as outlined below.
5.1. Trail Receptors
For example, loss of expression of the agonistic TRAIL receptors, TRAIL-R1 and TRAIL-R2, may account for TRAIL resistance. Both receptors are located on chromosome 8p, a region of frequent loss of heterozygosity (LOH) in tumors (28).
In a small percentage of cancers, for example, non-Hodgkin’s lymphoma, colorectal, breast, head and neck, or lung carcinoma, deletions or mutations were found, which resulted in loss of both copies of TRAIL-R1 and TRAIL-R2 (37–41). In addition, loss of TRAIL-R1 or TRAIL-R2 expression may be caused by epigenetic alterations such as promotor hypermethylation, for example, in neuroblastoma (42).
5.2. c-FLIP
TRAIL signaling can also be negative by intracellular proteins that associate with the cytoplasmatic domain of TRAIL receptors such as c-FLIP (43). c-FLIP has homology to caspase-8 and caspase-10 but lacks protease activity. By binding to FADD, c-FLIP prevents the interaction between the adaptor molecule FADD and procaspase-8. c-FLIP exists as a long c-FLIPL and a short c-FLIPS isoforms, both of which can inhibit death receptor-induced apoptosis. Interestingly, c-FLIPS was identified in a screen for genes that could confer resistance to TRAIL-induced apoptosis (44). High c-FLIP expression has been detected in many tumors and has been correlated with resistance to TRAIL-induced apoptosis, for example, in melanoma. However, a consistent correlation between c-FLIP expression and TRAIL resistance has not always been found (45). Importantly, downregulation of FLIP expression by inhibition of protein synthesis or RNA translation, cytotoxic drugs, proteasome inhibitors, PPAR ligand, or siRNAI for c-FLIP restored sensitivity for TRAIL-induced apoptosis in several cell types (46–48).
5.3. Bcl-2 Proteins
Bcl-2 family proteins play an important role in the regulation of the mitochondrial pathway, as these proteins localize to intracellular membranes such as the mitochondrial membrane (13). They comprise both antiapoptotic members, such as Bcl-2 or Bcl-XL, and proapoptotic molecules, such as Bax or Bid. Altered expression of Bcl-2 family proteins have been reported in various human cancers. Imbalances in the ratio of anti- and proapoptotic Bcl-2 proteins may favor tumor cell survival instead of cell death.
Overexpression of Bcl-2 or Bcl-XLblocked TRAIL-triggered apoptosis in many tumor cell lines, for example, prostate carcinoma, pancreatic carcinoma, neuroblastoma, or glioblastoma cells (49,50). In addition, gene ablation studies showed that Bax was absolutely required for TRAIL-induced apoptosis in colon carcinoma cells (44,51).
However, overexpression of Bcl-2 or Bcl-XL did not interfere with TRAIL-induced apoptosis in some cell types, for example, Jurkat or CEM T-cell leukemia cells (52).
Thus, the contribution of the mitochondrial pathway to TRAIL-induced apoptosis may depend on the cell type.
5.4. IAPs
The family of endogenous caspase inhibitors IAPs are highly conserved throughout evolution and comprise the human analogs XIAP, cIAP1, cIAP2, survivin, and livin
(ML-IAP) (53). IAPs have been reported to directly inhibit active caspase-3 and caspase-7 and to block caspase-9 activation. In addition to regulation of apoptosis, IAP members such as survivin are involved in the regulation of mitosis (54). The activity of IAPs are controlled at various levels, for example, by the transcription factor NFB that has been reported to stimulate expression of cIAP1, cIAP, and XIAP (53). In addition, Smac/Diablo and Omi, which are released from mitochondria upon apoptosis induction, neutralize IAPs through binding to IAPs thereby displacing them from their caspase partners (11). Increased IAPs expression is detected in many tumors and has been correlated with adverse prognosis (45,53). Importantly, overexpression of XIAP blocked TRAIL-triggered apoptosis in several cellular systems (55,56).
5.5. NFB
The transcription factor NFB has been connected with multiple aspects of oncoge- nesis, including cell proliferation or inhibition of apoptosis (57). NFB is composed of hetero- or homodimers of NFB/Rel family of proteins, which mediate protein dimerization, nuclear import, and specific DNA binding. In most cell types, NFB is sequestered in the cytoplasm by its interaction with IB proteins and therefore remains inactive. Upon stimulation, IB becomes phosphorylated following activation of the IKK complex and is degraded through the proteasome thereby releasing NFB to translocate into the nucleus for transcription of target genes. NFB target genes include several antiapoptotic proteins, for example, cIAP1, cIAP2, TRAF1, TRAF2, Bfl-1/A1, Bcl-XL, and FLIP. Interestingly, promotor activation of certain proapoptotic molecules of the TRAIL system including TRAIL-R1, TRAIL-R2, or TRAIL is also controlled by NFB consistent with reports that NFB can promote apoptosis under certain circum- stances (58,59). NFB is constitutively active in certain tumor types such as Hodgkin’s lymphoma or pancreatic carcinoma (57). Also, NFB activity is induced in response to various stimuli, for example, in response to cellular stress or anticancer agents. In addition, TRAIL can activate NFB, which is mediated by TRAIL-R1, TRAIL-R2, or TRAIL-R4 through a TRAF2-NIK-IKK/-dependent signaling cascade (18,60).
Interestingly, TRAIL has been reported to activate NFB especially under conditions, when apoptosis is blocked (61,62). Inhibition of NFB signaling, for example, by proteasome inhibitors, which prevent I B degradation, or by overexpresison of non- degradable IB mutants, has been reported to sensitize tumor cells for TRAIL-induced apoptosis, at least in some contexts (63).
6. TRAIL AND CANCER THERAPY 6.1. Safety of TRAIL Administration
The idea to specifically target death receptors to trigger apoptosis in tumor cells is attractive for cancer therapy as death receptors have a direct link to the cell’s death machinery (10). In addition, apoptosis upon death receptor ligation has been reported to occur independent of the p53 tumor suppressor gene, which is deleted or inactivated in more than half of human tumors (64). However, the clinical application of CD95 ligand or TNF is hampered by severe toxic side effects (30). Systemic adminis- tration of TNF or CD95 ligand causes a severe inflammatory response syndrome or massive liver cell apoptosis. In contrast, TRAIL appears to be a relatively safe and
promising candidate for clinical application, particularly in its non-tagged, zinc-bound homotrimeric form (28). Studies in non-human primates such as chimpanzees and cynomolgus monkeys showed no toxicity upon intravenous infusion, even at high doses (65). In addition, no cytotoxic activity of TRAIL was reported on various normal human cells of different lineages including fibroblasts, endothelial cells, smooth muscle cells, epithelial cells, or astrocytes (66). However, some concerns about potential toxic side effects on human hepatocytes or brain tissue have also been raised (67,68). The loss of tumor selectivity may be related to the TRAIL preparations used in these studies.
TRAIL preparations, which are antibody crosslinked or not optimized for Zn content, have been reported to form multimeric aggregates thereby overpassing the threshold of sensitivity of normal cells (28).
6.2. Antitumor Activity of TRAIL
Recombinant soluble TRAIL-induced apoptosis in a broad spectrum of cancer cell lines, including colon carcinoma, breast carcinoma, lung carcinoma, pancreas carcinoma, prostate carcinoma, renal carcinoma, thyroid carcinoma, malignant brain tumors, Ewing tumor, osteosarcoma, neuroblastoma, leukemia, and lymphoma (28,29).
Also, TRAIL exhibited potent tumoricidal activity in vivo in several xenograft models of colon carcinoma, breast carcinoma, malignant glioma, or multiple myeloma.
Furthermore, monoclonal antibodies that engage the TRAIL receptors, DR4 or DR5, also demonstrated potent antitumor activity against tumor cell lines and in preclinical cancer models (69,70).
6.3. Combination Therapy with TRAIL
Although these studies provided ample evidence of the potential of TRAIL for cancer therapy, many tumors remain refractory toward treatment with TRAIL, which has been related to the dominance of antiapoptotic signals. Importantly, numerous studies have shown that TRAIL synergized together with cytotoxic drugs or -irradiation to achieve antitumor activity in various cancers including malignant glioma, melanoma, leukemia, breast, colon, or prostate carcinoma (71–76). Remarkably, TRAIL and anticancer agents also cooperated to suppress tumor growth in different mouse models of human cancers. The molecular mechanisms, which account for this synergistic interaction, may include transcriptional upregulation of the agonistic TRAIL receptors, TRAIL-R1 and TRAIL-R2, which occurred in a p53-dependent or p53-independent manner (77,78). Of note, p53 has also been shown to transcriptionally activate the antagonistic TRAIL receptors, TRAIL-R3 and TRAIL-R4 (79). The synergistic inter- action between cytotoxic drugs and TRAIL may also be mediated by downregulation of antiapoptotic proteins such as Bcl-2, Bcl-XL, or FLIP upon drug treatment (80).
In addition, anticancer agents may sensitize tumor cells for TRAIL treatment by upregulating proapoptotic molecules including caspases or FADD (81). Caspase-8 expression is frequently impaired by hypermethylation in several tumors including neuroblastoma, Ewing tumors, malignant brain tumors, or lung carcinoma (82,83).
Importantly, restoration of caspase-8 expression by gene transfer or by demethylation treatment sensitized resistant tumor cells for TRAIL-induced apoptosis (83). Also, biological response modifiers such as IFN strongly enhanced the cytotoxic activity of TRAIL by upregulating caspase-8 expression in a STAT-1-dependent manner (84).
As TRAIL demonstrated synergistic interaction with anticancer agents or irradiation, TRAIL may be most effective in combination with conventional cancer treatments. In addition, small molecules may serve as molecular therapeutics to specifically target tumor cell resistance toward TRAIL in resistant forms of cancer. To this end, Smac agonists have recently been reported to potentiate the efficacy of TRAIL treatment by antagonizing the inhibitory effect of IAPs, which are overexpressed in many tumors (85). Importantly, Smac peptides synergized with TRAIL to eradicate malignant glioma in an orthotopic mouse model without any detectable toxicities to the normal brain tissue (85).
Aberrant architecture of the chromatin has been implicated in tumor formation and progression (86). Posttranslational modifications of histone proteins, in particular their acetylation status, control gene expression by regulating the accessibility of transcription factors to DNA (86). Histone acetylation is governed by the relative activities of histone acetyltransferases (HATs), which favor decompaction of the chromatin structure for efficient transcription, and histone deacetylases (HDACs), which remove acetyl groups from histone tails, thereby suppressing transcription (86).
HDAC inhibitors (HDACIs) have been reported to cause growth arrest, differenti- ation, and/or apoptosis by altering the transcription of a small and finite number of expressed genes (87). Interestingly, HDACIs were also found to significantly enhance the efficacy of TRAIL in various human cancers including breast, colon, lung or prostate carcinoma, mesothelioma, melanoma, as well as acute or chronic leukemia (88–101). The molecular basis for the HDACI-mediated sensitization for TRAIL has been linked to upregulation of TRAIL-R1 and/or TRAIL-R2 expression in a SP1- or NFB-dependent manner (88–92,94,97,100). In addition, the cooperative interaction of HDACI and TRAIL has been reported to involve redistribution of agonistic TRAIL receptors to membrane lipid rafts (99) or increased efficacy of TRAIL-induced death- inducing signaling complex (DISC) formation (89,91). Moreover, increased mitochon- drial damage (96,97), enhanced expression of proapoptotic molecules (96,97), or downregulation of antiapoptotic proteins, for example, Bcl-XL, Bcl-2, Mcl-1, FLIP, XIAP, or survivin (89,90,95,97), have been identified to lower the threshold for apoptosis induction by TRAIL in the presence of HDACI. Although HDACI in combination with TRAIL have been described to exert no or little toxicity on non- transformed cells such as peripheral blood lymphocytes or human mammary epithelial cells (93,94,97), there is recent evidence that HDACI may revert the lack of toxicity of TRAIL on non-transformed cells, for example, human renal proximal tubule epithelial cells (100). Thus, the question whether HDACI sensitize for TRAIL-induced apoptosis in a cancer-selective fashion has not yet been answered.
Most studies investigating the TRAIL sensitivity of tumor cells have so far been performed in vitro (29). Despite many limitations of cell-culture experiments, in vitro studies may reflect some of the important features of tumor treatment in vivo. Impor- tantly, experiments performed on primary cancer cells ex vivo in most cases yielded similar results. For example, combined treatment of primary cancer cells with TRAIL together with anticancer agents synergized in antitumor activity.
6.4. Tumor Surveillance
There is also mounting evidence for an important role of TRAIL in tumor surveil- lance, for example, from studies with TRAIL knockout mice (102,103). Although the
biology of the TRAIL system may differ significantly between mice and humans, as there is only one TRAIL receptor in mice, which is homologous to both TRAIL-R1 and TRAIL-R2, the phenotype of these knockout mice is informative with respect to the physiological function of TRAIL in vivo. Importantly, TRAIL-deficient mice were more susceptible to tumor metastasis than wild-type mice (103). These data are in accordance with studies showing an important role of NK cells, which constitu- tively express TRAIL, in the control of tumor metastasis (104,105). In addition, tumor formation induced by carcinogens was found to be enhanced in the presence of antag- onistic TRAIL antibodies (104). Thus, TRAIL may play an essential role as innate effector molecule in immune surveillance during tumor formation and progression.
7. CONCLUSIONS
Over the decade key elements of the TRAIL signaling pathway have been identified, and numerous studies provided substantial insights into the molecular mechanisms regulating TRAIL-induced apoptosis. The death ligand TRAIL is of special interest for cancer therapy because of its differential toxicity toward transformed versus normal cells. Importantly, TRAIL strongly synergized together with chemotherapy or irradi- ation in antitumor activity, even against some resistant forms of cancer.
However, several points remain to be addressed in future studies. As the tumor selective toxicity of TRAIL is presently not fully understood, further preclinical safety testing is necessary to assess the potential toxicity of TRAIL or agonistic TRAIL receptor antibodies on non-malignant tissues. In addition, the possible toxicity of TRAIL on normal tissues under conditions of combined treatment with anticancer agents or irradiation remains to be determined. Also, the molecular mechanisms leading to activation of survival pathways such as NFB or AKT upon treatment with TRAIL and their significance for cancer therapy are only partially understood. Moreover, the promise of TRAIL alone or in combination protocols remains to be tested in clinical settings. Future studies on the role of TRAIL in individual tumors both in vitro and in vivo in tumor cells of patients under chemotherapy, for example, by DNA microarrays or proteomic studies, may provide the basis for “tailored” tumor therapy with TRAIL and may identify new targets for therapeutic interventions.
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