Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation

doi:10.1016/j.ceb.2010.08.001

Current Opinion in Cell Biology

Volume 22, Issue 6, December 2010, Pages 837-844

https://doi.org/10.1016/j.ceb.2010.08.001 Get rights and content

Proapoptotic receptor agonists (PARAs) targeting death receptors (DRs) 4 and 5 hold promise for cancer therapy based on their selective ability to kill malignant versus healthy cells. Emerging clinical results have confirmed that DR4/5 PARAs are relatively well-tolerated and suitable for further investigation. Given that some cancer cell lines and models are not sensitive to PARAs, it is important to develop strategies to identify what specific types of tumor cells may be most responsive to PARA-based therapy and how to overcome apoptosis resistance mechanisms in tumors. Here we review the molecular and biological determinants of responsiveness to PARAs in cancer cells, and discuss the potential for predictive biomarkers and drug combination strategies to maximize the anti-tumor activity of these agents.

Section snippets

Background

Apoptosis plays an essential role in development, homeostasis, and tumor suppression. In mammalian cells, two major pathways, often referred to as the extrinsic and intrinsic pathways, contribute to apoptotic signaling. Both require activation of distinct initiator caspases that target downstream effector caspases, which cleave numerous cellular substrates culminating in the hallmark features of apoptosis: plasma membrane blebbing, nuclear condensation and DNA fragmentation. The intrinsic, or

Apo2L/TRAIL signaling — physiological role in tumor suppression?

Studies in mice suggest that the Apo2L/TRAIL pathway has a role in immune surveillance. Mice deficient in either Apo2L/TRAIL or mDR5 (the sole mouse ortholog of human DR4 and 5) show increased susceptibility to tumorigenesis and pathogen infection [3, 8]. In certain models, however, tumor development does not appear to be affected by mDR5 deficiency; for example, there was no impact on the incidence of lymphomas in p53-null mice or intestinal polyps in the APC^min model [9]. Tumors develop

PARAs — co-opting the Apo2L/TRAIL pathway for cancer therapy

Recombinant Apo2L/TRAIL (dulanermin) and agonistic monoclonal antibodies targeting DR4 or DR5 (Figure 1) may have broad potential for cancer therapy [7, 13]. Proapoptotic anti-tumor activity has been demonstrated in models reflecting diverse tumor types, both in vitro and in tumor xenograft settings. However, despite the wide expression of DR4 and DR5, various cancer cell lines and primary tumor isolates exhibit partial responsiveness or resistance to DR4 and DR5 agonists [14••, 15, 16, 17].

Role of death and decoy receptors in resistance to PARAs

DR4 and DR5 mRNAs are widely detected in healthy tissues [18]; however, protein expression appears restricted to damaged, infected, or malignant cells [19, 20]. Cell-surface levels of DR4 and DR5 do not generally correlate with tumor cell sensitivity to Apo2L/TRAIL signaling [14^••], although various agents can upregulate receptor expression and sensitize resistant tumor cells to PARAs [8, 21]. This suggests that low receptor density may be a relevant feature of tumor cell resistance. Indeed,

Defects within the DISC

The formation of a functional DISC is a central feature of DR signaling. Engagement of DR4 or DR5 by Apo2L/TRAIL or other agonists induces the recruitment of FADD and caspase-8 or caspase-10 to the plasma membrane. Additional requirements, including translocation of DISC components into membrane lipid rafts, facilitate receptor clustering and autocatalytic processing of the initiator caspase (Figure 1) [40]. These membrane-proximal events are critical for apoptotic signaling via the extrinsic

The mitochondrial apoptosis pathway in resistance to PARAs

In simplest terms, the mitochondrial apoptosis pathway is regulated by the balance of pro apoptotic versus anti apoptotic members of the Bcl-2 family. In most cancer cell lines, an effective apoptotic response to DR signaling requires signal amplification through the mitochondria. As such, alterations in the expression or function of the Bcl-2 family not only contribute to tumor development and chemoresistance, but also represent likely barriers to the therapeutic potential of PARAs.

The

Alternative signaling pathways–apoptosis friend or foe?

In addition to the primary DISC, engagement of DRs can induce a secondary signaling complex, containing core DISC components, as well as RIP1 and TRAF2 (Figure 1) [63]. This complex may activate additional signaling cascades, including the NF-κB, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38-mitogen activated protein kinase (MAPK) pathways [8, 64]. Many of these alternative signaling events have been proposed to counter proapoptotic activity, although there

Conclusions/perspective

The selective killing of malignant versus normal cells by PARAs targeting the Apo2L/TRAIL pathway provides a unique opportunity to investigate how best to harness the extrinsic apoptosis pathway for cancer therapy. Given that many cancers are inherently refractory to apoptosis activation, the successful clinical translation of PARAs will likely require better understanding of the most relevant determinants of sensitivity versus resistance. Insights from preclinical studies regarding predictive

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

References (70)

D. Brenner et al.
Mitochondrial cell death effectors
Curr Opin Cell Biol
(2009)
N. Ozoren et al.
Cell surface death receptor signaling in normal and cancer cells
Semin Cancer Biol
(2003)
L. Bin et al.
Tumor-derived mutations in the TRAIL receptor DR5 inhibit TRAIL signaling through the DR4 receptor by competing for ligand binding
J Biol Chem
(2007)
A. Elias et al.
Epigenetic silencing of death receptor 4 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in gliomas
Clin Cancer Res
(2009)
F.A. Greco et al.
Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer
Lung Cancer
(2008)
R.F. Kelley et al.
Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling
J Biol Chem
(2005)
H.N. LeBlanc et al.
Apo2L/TRAIL and its death and decoy receptors
Cell Death Differ
(2003)
D.A. Sharp et al.
Selective knockdown of the long variant of cellular FLICE inhibitory protein augments death receptor-mediated caspase-8 activation and apoptosis
J Biol Chem
(2005)
J.H. Song et al.
Lipid rafts and nonrafts mediate tumor necrosis factor related apoptosis-inducing ligand induced apoptotic and nonapoptotic signals in non small cell lung carcinoma cells
Cancer Res
(2007)
F.T. Liu et al.
Bortezomib blocks Bax degradation in malignant B cells during treatment with TRAIL
Blood
(2008)

B. Gillissen et al.

Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma

J Cell Biol

(2010)

X. Chen et al.

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

(2003)

S. Boehrer et al.

Prostate-apoptosis-response-gene-4 increases sensitivity to TRAIL-induced apoptosis

Leuk Res

(2006)

R. Burikhanov et al.

The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis

Cell

(2009)

D.L. Vaux et al.

IAPs, RINGs and ubiquitylation

Nat Rev Mol Cell Biol

(2005)

N.S. Wilson et al.

Death receptor signal transducers: nodes of coordination in immune signaling networks

Nat Immunol

(2009)

F. Gonzalvez et al.

New insights into apoptosis signaling by Apo2L/TRAIL

Oncogene

(2010)

D. Daniel et al.

Tumor necrosis factor: renaissance as a cancer therapeutic?

Curr Cancer Drug Targets

(2008)

A. Ashkenazi

Targeting death and decoy receptors of the tumour-necrosis factor superfamily

Nat Rev Cancer

(2002)

A. Ashkenazi

Directing cancer cells to self-destruct with pro-apoptotic receptor agonists

Nat Rev Drug Discov

(2008)

R.W. Johnstone et al.

The TRAIL apoptotic pathway in cancer onset, progression and therapy

Nat Rev Cancer

(2008)

H.H. Yue et al.

Loss of TRAIL-R does not affect thymic or intestinal tumor development in p53 and adenomatous polyposis coli mutant mice

Cell Death Differ

(2005)

G.P. Dunn et al.

Interferons, immunity and cancer immunoediting

Nat Rev Immunol

(2006)

E. Cretney et al.

Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice

J Immunol

(2002)

K. Takeda et al.

Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development

J Exp Med

(2002)

J. Wiezorek et al.

Death receptor agonists as a targeted therapy for cancer

Clin Cancer Res

(2010)

K.W. Wagner et al.

Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

Nat Med

(2007)

T. Naka et al.

Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with chemotherapeutic agents on patients’ colon tumors grown in SCID mice

Cancer Res

(2002)

J. Cheng et al.

Multiple mechanisms underlie resistance of leukemia cells to Apo2 Ligand/TRAIL

Mol Cancer Ther

(2006)

B.L. Hylander et al.

The anti-tumor effect of Apo2L/TRAIL on patient pancreatic adenocarcinomas grown as xenografts in SCID mice

J Transl Med

(2005)

J.P. Sheridan et al.

Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors

Science

(1997)

K. Ichikawa et al.

Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity

Nat Med

(2001)

E.L. Brincks et al.

CD8 T cells utilize TRAIL to control influenza virus infection

J Immunol

(2008)

B. Pennarun et al.

Playing the DISC: turning on TRAIL death receptor-mediated apoptosis in cancer

Biochim Biophys Acta

(2010)

P. Horak et al.

Contribution of epigenetic silencing of tumor necrosis factor-related apoptosis inducing ligand receptor 1 (DR4) to TRAIL resistance and ovarian cancer

Mol Cancer Res

(2005)

Cited by (115)

ALK inhibitors downregulate the expression of death receptor 4 in ALK-mutant lung cancer cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression
2023, Neoplasia (United States)
The successful treatment of patients with advanced non–small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) with ALK tyrosine kinase inhibitors (ALK-TKIs) represents a promising targeted therapy. As a result, various ALK-TKIs have been rapidly developed, some of which are approved while some are being tested in clinical trials. Death receptor 4 (DR4; also called TNFRSF10A or TRAIL-R1) is a cell surface protein, which functions as a pro-apoptotic protein that transduces TRAIL death signaling to trigger apoptosis. DR4 expression is positively regulated by MEK/ERK signaling and thus can be downregulated by MEK/ERK inhibition. This study thus focused on determining the effects of AKL-TKIs on DR4 expression and the underlying mechanisms. Three tested ALK-TKIs including APG-2449, brigatinib and alectinib effectively and preferentially inhibited Akt/mTOR as well as MEK/ERK signaling and decreased cell survival in ALK-mutant (ALKm) NSCLC cells with induction of apoptosis. This was also true for DR4 downregulation, which occurred even at 2 h post treatment. These ALK-TKIs did not affect DR4 protein stability, rather decreased DR4 mRNA expression. In parallel, they promoted degradation and reduced the levels of Fra-1 and c-Jun, two critical components of AP-1, and suppressed AP-1 (Fra-1/c-Jun)-dependent transcription/expression of DR4. Hence, it appears that ALK-TKIs downregulate DR4 expression in ALKm NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. Our findings thus warrant further investigation of the biological significance of DR4 downregulation in ALK-targeted cancer therapy.
MET inhibition downregulates DR4 expression in MET-amplified lung cancer cells with acquired resistance to EGFR inhibitors through suppressing AP-1-mediated transcription
2021, Neoplasia (United States)
Death receptor 4 (DR4) is a cell surface protein that is generally thought to mediate apoptosis upon binding to its ligand named TRAIL. However, its contribution to apoptosis resistance has also been reported. MET (or c-MET) gene amplification represents an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) against EGFR mutant non-small cell lung cancer (NSCLC). This study focuses on demonstrating the impact of MET inhibition on DR4 modulation in MET-amplified EGFR mutant NSCLC cell lines and the underlying mechanisms. Several MET inhibitors decreased DR4 levels in MET-amplified HCC827 cell lines resistant to EGFR-TKIs with no or limited effects on modulating DR5 levels, while increasing DR4 levels in HCC827 parental cells and other NSCLC cell lines. MET inhibitors did not affect DR4 stability, but decreased DR4 mRNA levels with suppression of AP-1-dependent DR4 promoter transactivation. Moreover, these inhibitors suppressed ERK and c-Jun phosphorylation accompanied with decreasing c-Jun levels. Hence, it is likely that MET inhibition downregulates DR4 expression in MET-amplified EGFR mutant NSCLC cells through suppressing AP-1-mediated DR4 transcription. Osimertinib combined with MET inhibition synergistically induces apoptosis in the MET-amplified EGFR mutant NSCLC cells accompanied with augmented DR4 reduction both in vitro and in vivo. Furthermore, MET inhibition combined with TRAIL enhanced killing of MET-amplified EGFR mutant HCC827/AR cells, but not HCC827 parental cells. These data collectively suggest that DR4 may possess an unrecognized anti-apoptotic function, contributing to apoptosis resistance under given conditions.
PARP goes the weasel! Emerging role of PARP inhibitors in acute leukemias
2021, Blood Reviews
Citation Excerpt :
Furthermore, IMGN632 when combined with talazoparib or olaparib was found to have synergistic in vitro effects against clinically annotated primary relapsed/refractory AML patient samples. Meng and colleagues reported that both olaparib and veliparib sensitize AML cell lines to TRAIL, the recombinant human tumor necrosis factor-related apoptosis inducing ligand [44] [45]. The human AML cell line ML-1 was treated for 24 h with veliparib and subsequently exposed to varying doses of recombinant human TRAIL agonist monoclonal antibodies, the natural ligand of the death receptor DR5.
Poly (ADP-ribose) polymerase (PARP) inhibitors, which induce synthetic lethality of BRCA mutant breast and ovarian cancers, are now under active exploration for treatment of acute leukemias, specifically acute myeloid leukemia (AML). Experimental data has revealed that DNA repair deficiencies similar to those found in BRCA mutant solid tumors function in malignant hematopoietic cells to enhance cell survival and promote therapy resistance. Preclinical studies have demonstrated that inhibition of PARP with a variety of agents can dramatically enhance the efficacy of other therapeutic approaches including cytotoxic and epigenetic chemotherapy, small molecule inhibitors (IDH and FLT3 inhibitors) and antibody drug conjugates. This has led to early stage clinical trials of multiple PARP inhibitors (PARPi) for AML patients. Despite small patient numbers, evidence of modest clinical efficacy and tolerability in combinatorial regimens support the further development of PARP inhibition as a novel therapeutic strategy for AML, particularly in select molecular subsets (MLL rearranged, FLT3 and IDH1 mutant disease.
Customizing a Tridomain TRAIL Variant to Achieve Active Tumor Homing and Endogenous Albumin-Controlled Release of the Molecular Machine in Vivo
2020, Biomacromolecules
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive antitumor drug candidate for precision cancer therapy due to its superior selective cytotoxicity in a variety of tumor cells. However, the clinical application of TRAIL in cancer therapy has been limited by its poor tumor-homing capacities and short half-life. Herein, we designed a tridomain TRAIL variant, Z-ABD-TRAIL, by sequentially fusing the platelet-derived growth factor receptor beta (PDGFRβ)-specific affibody Z_PDGFRβ and an albumin-binding domain (ABD) to the N-terminus of TRAIL. The fusion protein Z-ABD-TRAIL was produced as a soluble protein with high yield in Escherichia coli (E. coli). The Z_PDGFRβ domain provided Z-ABD-TRAIL with PDGFRβ-binding properties and thus promoted its tumor homing via the engagement of PDGFRβ-expressing pericytes on tumor microvessels. ABD-mediated binding of Z-ABD-TRAIL to albumin in the blood endowed TRAIL with long-lasting (>72 h for Z-ABD-TRAIL vs <0.5 h for TRAIL) abilities to kill tumor cells. Although the in vitro cytotoxicity of Z-ABD-TRAIL in tumor cells was similar to that of the parent TRAIL, the in vivo tumor uptake, apoptosis-inducing ability, and antitumor effect of Z-ABD-TRAIL were much greater than those of TRAIL, indicating that Z_PDGFRβ-mediated tumor homing and ABD-introduced albumin binding significantly improved the pharmacodynamics of TRAIL. In addition, repeated injection of high-dose Z-ABD-TRAIL showed no obvious acute toxicity in mice. These results demonstrate that the newly designed tridomain Z-ABD-TRAIL is a promising agent for precision cancer therapy.
Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment
2020, Journal of Controlled Release
The emergence of T-cell engineering with chimeric antigen receptors (CARs) has led to attractive therapeutics; however, autologous CAR-T cells are associated with poor clinical outcomes in solid tumors because of low safety and efficacy. Therefore, the aim of our study was to develop a CAR therapy with enhanced cytotoxicity against solid cancer using allogeneic NK cells. In this study, we engineered “off-the-shelf” NK cells to redirect them towards pancreatic ductal adenocarcinoma (PDAC) by improving their target-specific cytotoxic potential. By integrated bioinformatic and clinicopathological analyses, folate receptor alpha (FRα) and death receptor 4 (DR4) were significantly highly expressed in patient-derived tumor cells. The combined expression of FRα and DR4/5 was associated with inferior clinical outcomes, therefore indicating their use as potential targets for biomolecular treatment. Thus, FRα and DR4 expression pattern can be a strong prognostic factor as promising therapeutic targets for the treatment of PDAC. For effective PDAC treatment, allogeneic CAR-NK cells were reprogrammed to carry an apoptosis-inducing ligand and to redirect them towards FRα and initiate DR4/5-mediated cancer-selective cell death in FRα- and DR4/5-positive tumors. As a result, the redirected cytotoxic ligand-loaded NK cells led to a significantly enhanced tumor-selective apoptosis. Accordingly, use of allogeneic CAR-NK cells that respond to FRα and DR4/5 double-positive cancers might improve clinical outcomes based on personal genome profiles. Thus, therapeutic modalities based on allogeneic NK cells can potentially be used to treat large numbers of patients with optimally selective cytotoxicity.
Cell Death in the Origin and Treatment of Cancer
2020, Molecular Cell
Cell death, or, more specifically, cell suicide, is a process of fundamental importance to human health. Throughout our lives, over a million cells are produced every second. When organismal growth has stopped, to balance cell division, a similar number of cells must be removed. This is achieved by activation of molecular mechanisms that have evolved so that cells can destroy themselves. The first clues regarding the nature of one of these mechanisms came from studying genes associated with cancer, in particular the gene for BCL-2. Subsequent studies revealed that mutations or other defects that inhibit cell death allow cells to accumulate, prevent removal of cells with damaged DNA, and increase the resistance of malignant cells to chemotherapy. Knowledge of this mechanism has allowed development of drugs that kill cancer cells by directly activating the cell death machinery and by synergizing with conventional chemotherapy as well as targeted agents to achieve improved outcomes for cancer patients.

View all citing articles on Scopus

¹: Both these authors contributed equally to this paper.

View full text

Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation

Section snippets

Background

Apo2L/TRAIL signaling — physiological role in tumor suppression?

PARAs — co-opting the Apo2L/TRAIL pathway for cancer therapy

Role of death and decoy receptors in resistance to PARAs

Defects within the DISC

The mitochondrial apoptosis pathway in resistance to PARAs

Alternative signaling pathways–apoptosis friend or foe?

Conclusions/perspective

References and recommended reading

Curr Opin Cell Biol

Semin Cancer Biol

J Biol Chem

Clin Cancer Res

Lung Cancer

J Biol Chem

Cell Death Differ

J Biol Chem

Cancer Res

Blood

J Cell Biol

Cancer Res

Leuk Res

Cell

IAPs, RINGs and ubiquitylation

Nat Rev Mol Cell Biol

Death receptor signal transducers: nodes of coordination in immune signaling networks

Nat Immunol

New insights into apoptosis signaling by Apo2L/TRAIL

Oncogene

Tumor necrosis factor: renaissance as a cancer therapeutic?

Curr Cancer Drug Targets

Targeting death and decoy receptors of the tumour-necrosis factor superfamily

Nat Rev Cancer

Directing cancer cells to self-destruct with pro-apoptotic receptor agonists

Nat Rev Drug Discov

The TRAIL apoptotic pathway in cancer onset, progression and therapy

Nat Rev Cancer

Loss of TRAIL-R does not affect thymic or intestinal tumor development in p53 and adenomatous polyposis coli mutant mice

Cell Death Differ

Interferons, immunity and cancer immunoediting

Nat Rev Immunol

Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice

J Immunol

Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development

J Exp Med

Death receptor agonists as a targeted therapy for cancer

Clin Cancer Res

Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

Nat Med

Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with chemotherapeutic agents on patients’ colon tumors grown in SCID mice

Cancer Res

Multiple mechanisms underlie resistance of leukemia cells to Apo2 Ligand/TRAIL

Mol Cancer Ther

The anti-tumor effect of Apo2L/TRAIL on patient pancreatic adenocarcinomas grown as xenografts in SCID mice

J Transl Med

Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors

Science

Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity

Nat Med

CD8 T cells utilize TRAIL to control influenza virus infection

J Immunol

Playing the DISC: turning on TRAIL death receptor-mediated apoptosis in cancer

Biochim Biophys Acta

Contribution of epigenetic silencing of tumor necrosis factor-related apoptosis inducing ligand receptor 1 (DR4) to TRAIL resistance and ovarian cancer

Mol Cancer Res