FADD/MORT1 and Caspase-8 Are Recruited to TRAIL Receptors 1 and 2 and Are Essential for Apoptosis Mediated by TRAIL Receptor 2

Sprick, Martin R.; Weigand, Markus; Rieser, Eva; Rauch, Charles T.; Juo, Peter; Blenis, John; Krammer, Peter H.; Walczak, Henning

doi:10.1016/s1074-7613(00)80211-3

Cited by 727 publications

(608 citation statements)

References 58 publications

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“…The -800 -1200 +404 +2400 32 Perhaps, DAPK2 Figure 6 The transcription factor NF-kB is a critical component of DR5 expression and is necessary for the sensitisation to TRAIL-induced cell death seen after DAPK2 silencing. U2OS (a-e, l and m) and A549 (f-j, n and o) cells were transfected with either siNS or the following siRNA 1 : 1 mixes: siNF-kB1 þ siNS, siDAPK2 þ siNS and siDAPK2 þ NF-kB1 (40 nM in total).…”

Section: Discussionmentioning

confidence: 99%

DAPK2 is a novel modulator of TRAIL-induced apoptosis

Stöcker

et al. 2014

Cell Death Differ

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Targeting molecules involved in TRAIL-mediated signalling has been hailed by many as a potential magic bullet to kill cancer cells efficiently, with little side effects on normal cells. Indeed, initial clinical trials showed that antibodies against TRAIL receptors, death receptor (DR)4 and DR5, are well tolerated by cancer patients. Despite efficacy issues in the clinical setting, novel approaches to trigger TRAIL-mediated apoptosis are being developed and its clinical potential is being reappraised. Unfortunately, as observed with other cancer therapies, many patients develop resistance to TRAIL-induced apoptosis and there is thus impetuous for identifying additional resistance mechanisms that may be targetable and usable in combination therapies. Here, we show that the death-associated protein kinase 2 (DAPK2) is a modulator of TRAIL signalling. Genetic ablation of DAPK2 using RNA interference causes phosphorylation of NF-jB and its transcriptional activity in several cancer cell lines. This then leads to the induction of a variety of NF-jB target genes, which include proapoptotic DR4 and DR5. DR4 and DR5 protein expression is correspondingly increased on the cell surface and this leads to the sensitisation of resistant cells to TRAILinduced killing, in a p53-independent manner. As DAPK2 is a kinase, it is imminently druggable, and our data thus offer a novel avenue to overcome TRAIL resistance in the clinic. Despite the effort and resources invested in cancer research, cancer remains a serious public health problem. Most patients are treated surgically, with chemotherapeutic drugs and/or antibodies and small molecule inhibitors. Patients generally respond well to the initial therapy but frequently develop resistance to it. This poses a challenge to their treatment and calls for alternative approaches to be developed. Indeed, much excitement was generated in the mid-1990s when tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was identified. [1][2][3][4] TRAIL is a death receptor (DR) ligand that signals through DR4 and DR5, two members of the TNF receptor family. 5-7 DR5 has two isoforms that differ by 29 amino acids and which are functionally indistinguishable. 5,8 TRAIL ligation activates primarily the extrinsic apoptotic pathway. The formation of ligand/receptor complexes leads to the assembly of a multiprotein death-inducing signalling complex (DISC), which in the case of TRAIL is typically composed of the adaptor Fasassociated death domain, caspase-8, caspase-10 and/or c-FLIP. These initiator caspases proteolytically cleave effector caspases such as caspase-3, caspase-6 and/or caspase-7 thereby activating them. This leads to the destruction of key cellular components and the appearance of typical features of apoptosis. TRAIL can also activate intrinsic apoptotic pathways via BID and thus involve mitochondria. By virtue of preferentially killing tumour cells, TRAIL is seen by many as a 'magic bullet' against cancer cells. Some cancer cells, however, are resistant, or develop resistanc...

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Section: Discussionmentioning

confidence: 99%

DAPK2 is a novel modulator of TRAIL-induced apoptosis

Stöcker

et al. 2014

Cell Death Differ

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“…It was reported that Bid protein was activated by cleavage of precursor via activation of caspase 8 triggered by Trail in human B lymphoma BJAB cells and FasL in Jurkat T cells [11], [12]. It has been demonstrated that FADD and caspase 8 participate in the apoptotic signal pathway [13]. Our results suggested that the Trail induced cell death in Jurkat T cells might depend on the Bid activation resulted from Trail treatment caused caspase 8 activities, because Bcl-2 over-expression protected the Jurkat T cells from Trail induced apoptosis by competitively heterodimerizing with Bid protein.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 over-expression and activation of protein kinase C suppress the Trail-induced apoptosis in Jurkat T cells

Guo

2001

Cell Res

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Trail, a tumor necrosis factor-related apoptosis-inducing ligand, is a novel potent endogenous activator of the cell death pathway through the activation of cell surface death receptors Trail-R1 and Trail-R2. Its role, like FasL in activation-induced cell death (AICD), has been demonstrated in immune system. However the mechanism of Trail induced apoptosis remains unclear. In this report, the recombinant Trail protein was expressed and purified. The apoptosis-inducing activity and the regulation mechanism of recombinant Trail on Jurkat T cells were explored in vitro. Trypan blue exclusion assay demonstrated that the recombinant Trail protein actively killed Jurkat T cells in a dose-dependent manner. Trail-induced apoptosis in Jurkat T cells were remarkably reduced by Bcl-2 over expression in Bcl-2 gene transfected cells. Treatment with PMA (phorbol 12-myristate 13-acetate), a PKC activator, suppressed Trail-induced apoptosis in Jurkat T cells. The inhibition of apoptosis by PMA was abolished by pretreatment with Bis, a PKC inhibitor. Taken together, it was suggested that Bcl-2 over-expression and PMA activated PKC actively down-regulated the Trail-mediated apoptosis in Jurkat T cell.

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“…TRAIL binding to death receptors results in formation of a death-inducing signalling complex (DISC), consisting of death receptors, adaptor proteins, and procaspase 8, which leads to processing and activation of procaspase 8 by an autocatalytic mechanism (Sprick et al, 2000). Activated caspase 8 triggers the extrinsic apoptotic pathway by directly activating effectors such as caspase 3 and caspase 7, resulting in cleavage of downstream targets such as poly (ADPribose) polymerase (PARP).…”

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confidence: 99%

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

et al. 2005

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Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumour cells through activation of TRAIL-R1 and TRAIL-R2 death signalling receptors. Here, we describe the characterisation and activity of HGS-ETR1, the first fully human, agonistic TRAIL-R1 mAb that is being developed as an antitumour therapeutic agent. HGS-ETR1 showed specific binding to TRAIL-R1 receptor. HGS-ETR1 reduced the viability of multiple types of tumour cells in vitro, and induced activation of caspase 8, Bid, caspase 9, caspase 3, and cleavage of PARP, indicating activation of TRAIL-R1 alone was sufficient to induce both extrinsic and intrinsic apoptotic pathways. Treatment of cell lines in vitro with HGS-ETR1 enhanced the cytotoxicity of chemotherapeutic agents (camptothecin, cisplatin, carboplatin, or 5-fluorouracil) even in tumour cell lines that were not sensitive to HGS-ETR1 alone. In vivo administration of HGS-ETR1 resulted in rapid tumour regression or repression of tumour growth in pre-established colon, non-smallcell lung, and renal tumours in xenograft models. Combination of HGS-ETR1 with chemotherapeutic agents (topotecan, 5-fluorouracil, and irinotecan) in three independent colon cancer xenograft models resulted in an enhanced antitumour efficacy compared to either agent alone. Pharmacokinetic studies in the mouse following intravenous injection showed that HGS-ETR1 serum concentrations were biphasic with a terminal half-life of 6.9 -8.7 days and a steady-state volume of distribution of approximately 60 ml kg À1 . Clearance was 3.6 -5.7 ml À1 day À1 kg À1 . These data suggest that HGS-ETR1 is a specific and potent antitumour agent with favourable pharmacokinetic characteristics and the potential to provide therapeutic benefit for a broad range of human malignancies.

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FADD/MORT1 and Caspase-8 Are Recruited to TRAIL Receptors 1 and 2 and Are Essential for Apoptosis Mediated by TRAIL Receptor 2

Cited by 727 publications

References 58 publications

DAPK2 is a novel modulator of TRAIL-induced apoptosis

DAPK2 is a novel modulator of TRAIL-induced apoptosis

Bcl-2 over-expression and activation of protein kinase C suppress the Trail-induced apoptosis in Jurkat T cells

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

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