New insights into apoptosis signaling by Apo2L/TRAIL

Gonzalvez, François; Ashkenazi, Avi

doi:10.1038/onc.2010.221

Cited by 321 publications

(310 citation statements)

References 173 publications

(199 reference statements)

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“…2 TRAIL has also a crucial role in Con A-induced hepatitis. 3 TRAIL activates apoptosis by binding to death receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) 4 in humans and only to mDR5 (mTRAIL-R2/mKILLER) in mice. 5 Besides apoptosis induction, TRAIL induces necrosis in Jurkat cells 6 or in murine prostate adenocarcinoma TRAMP-C2 cells.…”

Section: Tumor Necrosis Factor (Tnf)-related Apoptosis Inducing Liganmentioning

confidence: 99%

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

et al. 2012

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Although TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is a well-known apoptosis inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAILinduced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL-induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis.

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Section: Tumor Necrosis Factor (Tnf)-related Apoptosis Inducing Liganmentioning

confidence: 99%

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

et al. 2012

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“…2 Mechanistically, apoptosis induction by TRAIL, as for other ligands of the TNF family, occurs via receptor clustering. 14 Under physiologic conditions, TRAIL is expressed as a noncovalently associated homotrimeric membrane protein, from which it is proteolytically cleaved into a soluble, homotrimeric form. In vitro, both the membrane and the soluble forms are, in principle, able to induce apoptosis, albeit with different efficiency and, depending on cell type, via distinct receptors.…”

Section: Introductionmentioning

confidence: 99%

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

Siegemund

Seifert

Zarani³

et al. 2016

mAbs

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Fusion proteins combining oligomeric assemblies of a genetically obtained single-chain (sc) variant of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with antibodies directed against tumorassociated antigens represent a promising strategy to overcome the limited therapeutic activity of conventional soluble TRAIL. To further improve the scTRAIL module in order to obtain a robust, thermostable molecule of high activity, we performed a comprehensive analysis of the minimal TNF homology domain (THD) and optimized linkers between the 3 TRAIL subunits constituting a scTRAIL. Through a stepwise mutagenesis of the N-and C-terminal region and the joining linker sequences, we generated bioactive scTRAIL molecules comprising a covalent linkage of the C-terminal Val280 and the Nterminal position 122 by only 2 amino acid residues in combination with conservative exchanges at positions 122 and 279. The increased thermal stability and solubility of such optimized scTRAIL molecules translated into increased bioactivity in the diabody-scTRAIL (Db-scTRAIL) format, exemplified here for an epidermal growth factor receptor-specific Db-scTRAIL. Additional modifications within the diabody linkers resulted in a fusion protein exerting high, target-dependent apoptosis induction in tumor cell lines in vitro and potent antitumor activity in vivo. Our results illustrate that protein engineering of scTRAIL and associated peptide linkers provides a promising strategy to develop antibody-scTRAIL fusion proteins as effective antitumor therapeutics.

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“…[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][6][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.…”

mentioning

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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New insights into apoptosis signaling by Apo2L/TRAIL

Cited by 321 publications

References 173 publications

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

DAPK2 is a novel modulator of TRAIL-induced apoptosis

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