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Biochemistry, Genetics and Molecular Biology » "Autophagy in Current Trends in Cellular Physiology and Pathology", book edited by Nikolai V. Gorbunov and Marion Schneider, ISBN 978-953-51-2727-7, Print ISBN 978-953-51-2726-0, Published: November 10, 2016 under CC BY 3.0 license. © The Author(s).

Chapter 6

TRAIL Induces Apoptosis and Autophagy

By Zhenyu Yao and Dexian Zheng
DOI: 10.5772/64246

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TRAIL Induces Apoptosis and Autophagy

Zhenyu Yao and Dexian Zheng
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It is known that tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) could induce both apoptosis and autophagy. Here, we summarized the recent findings of the key regulators and the crosstalk pathway that highlights the intricate interplay between TRAIL‐induced apoptosis and autophagy.

Keywords: apoptosis, autophagy, caspase‐8, RIP1, TRAIL

1. Introduction

Tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL), also known as Apo‐2 ligand (Apo2L), is a multifunctional cytokine of the TNF superfamily (TNFSF) [1, 2]. TRAIL gained much attention due to its specific antitumor potential without toxic side effects [3], making TRAIL itself as well as agonists of its two receptors, which can submit an apoptotic signal, TRAIL‐R1 (DR4) [4] and TRAIL‐R2 (DR5) [58], promising novel biotherapeutics for cancer therapy [911]. Importantly, TRAIL can also induce autophagy, which has been linked to apoptosis, serving either a prosurvival or prodeath function [12, 13]. Recent findings reveal that the cellular contexts require a balanced interplay between apoptosis and autophagy. Here, we summarized the recent findings of the key regulator and the crosstalk pathway that highlights the intricate interplay between TRAIL‐induced apoptosis and autophagy.

2. TRAIL‐induced apoptosis and autophagy

2.1. TRAIL signaling

There are four TRAIL transmembrane receptors: TRAIL‐R1 (DR4), TRAIL‐R2 (DR5), TRAIL‐R3, also known as decoy receptor 1 (DcR1), and TRAIL‐R4 (DcR2), and a soluble receptor osteoprotegerin (OPG) [4, 7, 14]. Only TRAIL‐R1 and TRAIL‐R2 are able to induce apoptosis, whereas TRAIL‐R3, TRAIL‐R4, and OPG lack the intracellular functional domain, which is required for apoptosis induction [15, 16]. This domain is characteristic for all apoptosis‐inducing members of the TNFR superfamily (SF) and is called the death domain (DD). TRAIL‐R3 and TRAIL‐R4 have been suggested to act as decoy receptors that inhibit apoptosis induction [17]. It has been delineated that TRAIL triggers two major apoptosis signaling pathways, the death receptor (extrinsic) and the mitochondrial (intrinsic) pathways. TRAIL triggers the extrinsic apoptosis pathway upon binding of the TRAIL trimer to TRAIL‐R1 and/or TRAIL‐R2, resulting in receptor trimerization, which in turn leads to recruitment of the adaptor protein Fas‐associated DD (FADD). FADD in turn recruits procaspase‐8 and procaspase‐10 through homotypic interactions of death‐effector domains (DED) presenting in FADD and caspase‐8 and caspase‐10, respectively. This multiprotein complex is called death‐inducing signaling complex (DISC) [1821]. The DISC is an aggregation of the intracellular death domain of the death receptor. In “type I” cells, the procaspase‐8 and procaspase‐10 form homodimers. This induces a conformational change that exposes their proteolytical active sites, resulting in autoactivation and subsequent cleavage of additional procaspase‐8 and procaspase‐10 molecules leading to activation of sufficient caspase‐8 to stimulate effector caspase‐3 to induce apoptosis [2224]. However, “type II” cells generate less‐active caspase‐8 at the DISC. These cells induce apoptosis requiring further signal amplification by the intrinsic/mitochondrial pathway. In this situation, an intracellular complex is activated [2527]. The next is triggered by caspase‐8‐mediated cleavage of Bid to truncated Bid (tBid) as the active fragment of this protein [2831]. Subsequently, tBid activates the mitochondrial pathway eventually leading to mitochondrial outer membrane permeabilization (MOMP) and releasing of cytochrome C and Smac/DIABLO [30, 32]. In the cytosol, cytochrome c Apaf‐1 and caspase‐9v forms a multimeric complex called apoptosome. Activated caspase‐9 as the initiator caspase cleaves and activates the effector caspases. Release of Smac augments apoptosis by antagonizing the inhibitor of apoptosis (IAP) proteins, a family of antiapoptotic proteins that block apoptosis by binding to and inhibiting effector caspases such as caspase‐3 and caspase‐7 [33, 34].

In the DISC, the main regulator protein is cellular FLICE‐like inhibitory protein (cFLIP) and caspase‐8, cFLIP contains a death domain, which allows them to interact with proteins of the TRAIL DISC, thereby blocking the transmission of the proapoptotic signal and preventing caspase‐8 activation [3537]. cFLIP closely resembles caspase‐8 but lacks the protease activity required for apoptosis induction [38, 39]. Two main variants of cFLIP are expressed on the protein level: a short isoform (cFLIP‐S) and a long isoform (cFLIP‐L) [40]. The cFLIP‐S isoform can inhibit caspase‐8 activation in a dominant‐negative manner by competing with it for binding to FADD. cFLIP‐L can also completely prevent DR‐induced apoptosis when it is expressed at high levels. Several studies have demonstrated that cancer cells exploit overexpression of cFLIP to evade TRAIL‐induced apoptosis [4143]. Overexpression of cFLIP is a frequent event in human cancers and has been correlated with resistance to the induction of apoptosis, including TRAIL‐mediated cell death [36, 37]. Consequently, downregulation of cFLIP may sensitize certain cancers to TRAIL‐induced apoptosis [4446]. Another key regulator in the DISC is caspase‐8 that, besides caspase‐10, represents the initiator caspase that is engaged during TRAIL‐induced apoptosis [47]. Hypermethylation of a regulatory motif that controls caspase‐8 expression has been shown to be responsible for low or even absent caspase‐8 expression in several cancer entities, resulting in resistance or decreased sensitivity to TRAIL‐induced apoptosis [4851]. Caspase‐8 function can be suppressed in a dominant‐negative manner by aberrant expression of a splice variant of caspase‐8, that is, caspase‐8 long (caspase‐8L) [52, 53]. This variant of caspase‐8 was detected in cancer cells. Caspase‐8L interferes with caspase‐8 activation by competing with wild‐type caspase‐8 for the recruitment into the TRAIL DISC. Additional regulatory mechanisms that control caspase‐8 activity include post‐translational alterations of caspase‐8 such as phosphorylation. The tyrosine kinase Src has been reported to phosphorylate caspase‐8 on one specific residue (tyrosine‐308), which impairs the enzymatic function of caspase‐8 [54]. These regulation factors can influence the activity of caspase‐8 that causes the change of TRAIL‐induced apoptosis.

Except from inducing apoptosis, TRAIL can also induce cell survival signaling such as proinflammatory pathways (through NF‐kB, Akt, MAPK, and JNK activation). TRAIL can promote a variety of cell survival cascades leading, for example, to proliferation, migration, invasion, and even metastasis, especially in cancers in which the cell death signaling part of the signaling network is impaired [5557]. The induction of pathways has been suggested to be mediated by the formation of a secondary complex containing FADD, caspase‐8, cFLIP, RIP1, TRAF2, and NEMO [25, 58]. RIP1 is an important regulatory protein in the DISC that can activate NF‐κB and caspase‐8 and generate reactive oxygen species (ROS) [5961]. RIP1 function is modulated by ubiquitination and phosphorylation [62, 63]; a previous report showed that in TNF‐α‐induced DISC, RIP1, and NEMO form a stable chain of linear ubiquitin. This complex is involved in determining cell survival, necrosis, and apoptosis [64].

2.2. The regulators and pathways in TRAIL‐induced apoptosis and autophagy

Apoptosis and autophagy are evolutionarily conserved processes that regulate cell fate together. Although apoptosis and autophagy has obvious difference, but their regulation is closely related; they share the same regulator molecules and same pathway; however, these same regulators may determine a different cell fate.

Nowadays, most studies focused on the relationship between TRAIL sensitivity and autophagy [12, 6568], TRAIL has been shown to induce apoptosis and autophagy in a number of cancer cell lines, including colon, glioma, bladder and prostate, and breast carcinoma. Han et al. first explained TRAIL‐mediated cytoprotective autophagy in apoptosis‐deficient tumor cells. They found that TRAIL can induce autophagic response in apoptosis‐defective tumor cells (Hct116‐FLIP or Bax-/- Hct116). Engineered apoptotic deficiencies included stable FLIP transfection, which is expected to block the TRAIL‐apoptotic cascade at the DISC level, and Bax knockout demonstrated to block the TRAIL apoptotic response of colon carcinoma Hct116 cells despite the processing of caspase‐8 upstream of the mitochondria. Inhibition of autophagy by the knockdown of Beclin 1, UVRAG, Vps34, or Atg7 allows for the induction of significant apoptosis in response to TRAIL [69]. The following work from this laboratory demonstrates that TRAIL‐mediated autophagic response counterbalances the TRAIL‐mediated apoptotic response by the continuous sequestration of the large caspase‐8 subunit in autophagosomes and its subsequent elimination in lysosome [66]. Inhibition of autophagy induces caspase‐8 activity; these findings provide evidence for regulation of caspase activity by autophagy. These results suggest that the regulators, such as Beclin 1 and caspase‐8, play an important role in the regulation of TRAIL‐induced apoptosis and autophagy.

He et al. demonstrate that TRAIL induced cytoprotective autophagy in different cancer cell lines. MAPK8/JNK activation mediated by TRAF2 and RIP1 is required for TRAIL‐induced autophagy. Blocking MAPK8 but not NF‐κB effectively blocked autophagy, suggesting that MAPK8 is the main pathway for TRAIL‐induced autophagy. TRAF2 and RIP1 modulated TRAIL‐induced and MAPK8‐mediated autophagy. These results reveal that inhibiting MAPK8 pathway‐mediated autophagy will increase TRAIL's anticancer activity in cancer cells [65]. Inhibition of antiapoptosis factors in the DISC (cIAP1, cIAP2, XIAP, and c‐FLIP, and so on) increases TRAIL‐induced apoptosis. Also, some autophagy‐related pathways, such as AMPK and MAPK/JNK pathway, are involved in TRAIL‐induced apoptosis [65, 70, 71]. These results suggest that there are some regulators and pathways that are necessary for autophagy involved in the regulation of TRAIL‐induced apoptosis and autophagy.

Following these researches, some new regulators were found. Caspase‐9 is a novel coregulator of apoptosis and autophagy. Han et al. demonstrate that caspase‐9 facilitates the early events leading to autophagosome formation; that it forms a complex with Atg7, and Atg7 represses the apoptotic capability of caspase‐9, whereas the latter enhances the Atg7‐mediated formation of light chain 3‐II. The repression of caspase‐9 apoptotic activity is mediated by its direct interaction with Atg7, and it is not related to the autophagic function of Atg7. The Atg7 caspase‐9 complex performs a dual function of linking caspase‐9 to the autophagic process while keeping in check its apoptotic activity [72]. So far it has been found that many regulators such as Beclin 1 and caspase 8 IAPs XIAP in TRAIL induced apoptosis and autophagy in cancer cells. Caspase‐8L, cFLIP‐L, and cFLIP‐S act not only as antiapoptotic factors but also as suppressors of autophagy. Inhibition of autophagy by gene silencing of these regulators or small compounds targets these regulators sensitizing TRAIL‐resistant tumor cells to TRAIL‐induced apoptosis. Taken together, these researches suggest some potential targets in the prediction of tumor resistance to DR‐targeted therapies. Interestingly, a basal level of autophagy is needed for TRAIL‐induced apoptosis [73].

In addition to cancer cells, TRAIL has been shown to induce apoptosis and autophagy in other cell lines such as U937 cell, Jurkat T cell, breast epithelial cells, and so on. We found that TRAIL induces both apoptosis and autophagy in human U937 cells [74]. Inhibition of autophagy facilitates TRAIL‐induced apoptosis, suggesting that autophagy of macrophages protects against TRAIL‐induced apoptosis. RIP1 ubiquitination rapidly increased in U937 cells treated with TRAIL, and RIP1 ubiquitination was significantly reduced in the presence of 3‐MA in the cells treated with TRAIL. RIP1 expression was also distinctly decreased in the presence of 3‐MA in the cells treated with TRAIL. Furthermore, c‐FLIP‐L cleaved into the p43 variant caspase‐8 was degraded into p43/41 while autophagy was suppressed by 3‐MA in the cells treated with TRAIL. Knockdown of RIP1 suppresses autophagy in macrophage. These data demonstrate that RIP1 is essential for the regulation of death receptor‐mediated apoptosis and autophagy in macrophage and suggest that the expression and ubiquitination of RIP1 regulate TRAIL‐induced apoptosis and autophagy. The results in this study contribute to understanding the regulation of apoptosis and autophagy in macrophages, and sheds light on inflammation and autoimmune diseases [74].

Wang et al. in our group demonstrate that HTLV‐1 (human T cell leukemia virus type 1) Tax protein increases autophagosome accumulation in human U251 astroglioma cells. In addition, HTLV‐1 Tax deregulated the autophagy pathway, which plays a protective role during the death receptor‐mediated apoptosis. Tax‐induced c‐FLIP expression also contributes to the resistance against death receptor‐mediated apoptosis. Tax‐induced c‐FLIP expression correlated with the phosphorylation of IKK and the transcriptional activation of NF‐κB. But Tax‐triggered autophagy only depends on the activation of IKK but not on the activation of NF‐kB. TRAIL‐induced apoptosis is correlated with the degradation of Tax, which can be facilitated by the inhibitors of autophagy [75]. These results outline a complex regulatory network between apoptosis and autophagy, and Tax‐induced autophagy represents a new potential target for therapeutic intervention for the HTVL‐1‐related diseases.

Herrero‐Martin et al. demonstrate that TRAIL triggers cytoprotective autophagy in untransformed human epithelial cells by the AMP‐activated protein kinase pathway. Transforming growth factor‐b‐activating kinase 1 (TAK1) and TAK1‐binding subunit 2 mediate TRAIL‐induced activation of AMPK and autophagy. These data have broad implications for understanding the cellular control of energy homoeostasis as well as the resistance of untransformed cells against TRAIL‐induced apoptosis [71]. These studies of macrophage, Jurkat T cell, and breast epithelial cells have shown that some new regulators are involved in TRAIL‐induced apoptosis and autophagy, and the expression and ubiquitination of RIP1, HTLV‐1 Tax protein, and TAK1‐AMPK pathway regulate the balance of TRAIL‐induced apoptosis and autophagy in different extent.

3. Conclusion

Taken together, both the regulators in apoptosis pathway such as caspase‐8 and caspase‐9 and the key factors in autophagy such as Beclin 1 and ATG7 can regulate the TRAIL‐induced apoptosis and autophagy [66, 72]. Moreover, some molecular switchers, like RIP1, regulate the balance between TRAIL‐induced apoptosis and autophagy by dynamic expression and modification [65, 74]. They share the same regulators even pathways to control the complicated process (Table 1).

Both apoptosis and autophagy are important biological processes that play essential roles in the development of tissue homeostasis and disease. Interactions among components of the two pathways indicate a complex crosstalk. Insight into the complex network of TRAIL‐induced apoptosis and autophagy contributes to the development of novel therapeutic strategies for the treatment of TRAIL‐related diseases and deeply understand the molecular mechanism of apoptosis and autophagy.

Cell linesKey regulators pathwayReferences
Hct116‐FLIP or (Bax-/-)Hct116Beclin 1 and caspase‐8[66, 69]
UM‐UC‐3, PC‐3, and A549TRAF2 (RIP1)‐MAPK8/JNK pathway[65]
Hct116, HeLa, MB‐MDA‐231, and RKOAtg7·caspase‐9 complex[72]
U937RIP1 caspase‐8 and cFLIP[74]
U251HTLV‐1 Tax and cFLIP[75]
MCF10A–eGFP–LC3TAK1‐AMPK pathway[71]

Table 1.

The regulators and pathways in TRAIL‐induced apoptosis and autophagy in differences cell lines.


1 - Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo‐2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996;271:12687–12690. DOI: 10.1074/jbc.271.22.12687
2 - Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995;3:673–682. DOI:10.1016/1074‐7613(95)90057‐8
3 - Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor‐related apoptosis‐inducing ligand in vivo. Nat Med 1999; 5:157–163. DOI:10.1038/5517
4 - Pan G, O'Rourke K, Chinnaiyan AM, et al. The receptor for the cytotoxic ligand TRAIL. Science 1997; 276:111–113. DOI: 10.1126/science.276.5309.111
5 - Schneider P, Bodmer JL, Thome M, Hofmann K, Holler N, Tschopp J. Characterization of two receptors for TRAIL. FEBS Lett 1997; 416:329–334. DOI: 10.1016/S0014‐5793(97)01231‐3
6 - MacFarlane M, Ahmad M, Srinivasula SM, Fernandes‐Alnemri T, Cohen GM, Alnemri ES. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J Biol Chem 1997;272:25417–25420. DOI: 10.1074/jbc.272.41.25417
7 - Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L. Death receptor 5, a new member of the TNFR family, and DR4 induce FADD‐dependent apoptosis and activate the NF‐kappaB pathway. Immunity 1997; 7:821–830. DOI:10.1016/S1074‐7613(00)80400‐8
8 - Walczak H, Degli‐Esposti MA, Johnson RS, et al. TRAIL‐R2: a novel apoptosis‐mediating receptor for TRAIL. EMBO J 1997; 16:5386–5397. DOI:10.1093/emboj/16.17.5386
9 - Micheau O, Shirley S, Dufour F. Death receptors as targets in cancer. Br J Pharmacol 2013; 169:1723–1744. DOI:10.1111/bph.12238
10 - Lim B, Allen JE, Prabhu VV, Talekar MK, Finnberg NK, El‐Deiry WS. Targeting TRAIL in the treatment of cancer: new developments. Expert Opin Ther Targets 2015; 19:1171–1185. DOI:10.1517/14728222.2015.1049838
11 - Refaat A, Abd‐Rabou A, Reda A. TRAIL combinations: the new ‘trail’ for cancer therapy (Review). Oncol Lett 2014; 7:1327–1332. DOI:10.3892/ol.2014.1922
12 - Mills KR, Reginato M, Debnath J, Queenan B, Brugge JS. Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc Natl Acad Sci U S A 2004; 101:3438–3443. DOI:10.1073/pnas.0400443101
13 - Park KJ, Lee SH, Kim TI, et al. A human scFv antibody against TRAIL receptor 2 induces autophagic cell death in both TRAIL‐sensitive and TRAIL‐resistant cancer cells. Cancer Res 2007; 67:7327–7334. DOI:10.1158/0008‐5472.CAN‐06‐4766
14 - Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998; 273:14363–14367. DOI: 10.1074/jbc.273.23.14363
15 - Degli‐Esposti MA, Smolak PJ, Walczak H, et al. Cloning and characterization of TRAIL‐R3, a novel member of the emerging TRAIL receptor family. J Exp Med 1997; 186:1165–1170. DOI: 10.1084/jem.186.7.1165
16 - Degli‐Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG. The novel receptor TRAIL‐R4 induces NF‐kappaB and protects against TRAIL‐mediated apoptosis, yet retains an incomplete death domain. Immunity 1997; 7:813–820. DOI:10.1016/S1074‐7613(00)80399‐4
17 - Merino D, Lalaoui N, Morizot A, Schneider P, Solary E, Micheau O. Differential inhibition of TRAIL‐mediated DR5‐DISC formation by decoy receptors 1 and 2. Mol Cell Biol 2006;26:7046–7055. DOI:10.1128/MCB.00520‐06
18 - Bodmer JL, Holler N, Reynard S, et al. TRAIL receptor‐2 signals apoptosis through FADD and caspase‐8. Nat Cell Biol 2000; 2:241–243. DOI:10.1038/35008667
19 - Kuang AA, Diehl GE, Zhang J, Winoto A. FADD is required for DR4‐ and DR5‐mediated apoptosis: lack of trail‐induced apoptosis in FADD‐deficient mouse embryonic fibroblasts. J Biol Chem 2000; 275:25065–25068. DOI:10.1074/jbc.C000284200
20 - Peter ME. The TRAIL DISCussion: it is FADD and caspase‐8! Cell Death Differ 2000; 7:759–760. DOI:10.1038/sj.cdd.4400735
21 - Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A. Apo2L/TRAIL‐dependent recruitment of endogenous FADD and caspase‐8 to death receptors 4 and 5. Immunity 2000; 12:611–620. DOI:10.1016/S1074‐7613(00)80212‐5
22 - Chen M, Wang J. Initiator caspases in apoptosis signaling pathways. Apoptosis 2002; 7:313–319. DOI:10.1023/A:1016167228059
23 - Muhlethaler‐Mottet A, Flahaut M, Bourloud KB, et al. Individual caspase‐10 isoforms play distinct and opposing roles in the initiation of death receptor‐mediated tumour cell apoptosis. Cell Death Dis 2011; 2:e125. DOI:10.1038/cddis.2011.8
24 - Salvesen GS, Dixit VM. Caspase activation: the induced‐proximity model. Proc Natl Acad Sci U S A 1999; 96:10964–10967. DOI:10.1016/j.cell.2004.06.007
25 - Varfolomeev E, Maecker H, Sharp D, et al. Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor‐related apoptosis‐inducing ligand. J Biol Chem 2005; 280:40599–40608. DOI:10.1074/jbc.M509560200
26 - Ozoren N, El‐Deiry WS. Defining characteristics of Types I and II apoptotic cells in response to TRAIL. Neoplasia 2002; 4:551–557. DOI:10.1038/sj.neo.7900270
27 - Rudner J, Jendrossek V, Lauber K, Daniel PT, Wesselborg S, Belka C. Type I and type II reactions in TRAIL‐induced apoptosis ‐‐ results from dose‐response studies. Oncogene 2005; 24:130–140. DOI:10.1038/sj.onc.1208191
28 - Grinberg M, Sarig R, Zaltsman Y, et al. tBID Homooligomerizes in the mitochondrial membrane to induce apoptosis. J Biol Chem 2002; 277:12237–12245. DOI:10.1074/jbc.M104893200
29 - Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94:491–501. DOI:10.1016/S0092‐8674(00)81590‐1
30 - Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998; 94:481–490. DOI:10.1016/S0092‐8674(00)81589‐5
31 - Wei MC, Lindsten T, Mootha VK, et al. tBID, a membrane‐targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000; 14:2060–2071. DOI:10.1101/gad.14.16.2060
32 - Baliga B, Kumar S. Apaf‐1/cytochrome c apoptosome: an essential initiator of caspase activation or just a sideshow? Cell Death Differ 2003; 10:16–18. DOI:10.1038/sj.cdd.4401166
33 - Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. The c‐IAP‐1 and c‐IAP‐2 proteins are direct inhibitors of specific caspases. EMBO J 1997; 16:6914–6925. DOI:10.1093/emboj/16.23.6914
34 - Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X‐linked IAP is a direct inhibitor of cell‐death proteases. Nature 1997; 388:300–304. DOI:10.1038/40901
35 - Fulda S. Targeting c‐FLICE‐like inhibitory protein (CFLAR) in cancer. Expert Opin Ther Targets 2013; 17:195–201. DOI:10.1517/14728222.2013.736499
36 - Haag C, Stadel D, Zhou S, et al. Identification of c‐FLIP(L) and c‐FLIP(S) as critical regulators of death receptor‐induced apoptosis in pancreatic cancer cells. Gut 2011; 60:225–237. DOI:10.1136/gut.2009.202325
37 - Longley DB, Wilson TR, McEwan M, et al. c‐FLIP inhibits chemotherapy‐induced colorectal cancer cell death. Oncogene 2006; 25:838–848. DOI:10.1038/sj.onc.1209122
38 - Irmler M, Thome M, Hahne M, et al. Inhibition of death receptor signals by cellular FLIP. Nature 1997; 388:190–195. DOI:10.1038/40657
39 - Tschopp J, Irmler M, Thome M. Inhibition of fas death signals by FLIPs. Curr Opin Immunol 1998; 10:552–558. DOI:10.1016/S0952‐7915(98)80223‐9
40 - Krueger A, Schmitz I, Baumann S, Krammer PH, Kirchhoff S. Cellular FLICE‐inhibitory protein splice variants inhibit different steps of caspase‐8 activation at the CD95 death‐inducing signaling complex. J Biol Chem 2001; 276:20633–20640. DOI:10.1074/jbc.M101780200
41 - Burns TF, El‐Deiry WS. Identification of inhibitors of TRAIL‐induced death (ITIDs) in the TRAIL‐sensitive colon carcinoma cell line SW480 using a genetic approach. J Biol Chem 2001; 276:37879–37886. DOI:10.1074/jbc.M103516200
42 - Riley JS, Hutchinson R, McArt DG, et al. Prognostic and therapeutic relevance of FLIP and procaspase‐8 overexpression in non‐small cell lung cancer. Cell Death Dis 2013; 4:e951. DOI:10.1038/cddis.2013.481
43 - Guseva NV, Rokhlin OW, Taghiyev AF, Cohen MB. Unique resistance of breast carcinoma cell line T47D to TRAIL but not anti‐Fas is linked to p43cFLIP(L). Breast Cancer Res Treat 2008; 107:349–357. DOI:10.1007/s10549‐007‐9563‐2
44 - Geserick P, Drewniok C, Hupe M, et al. Suppression of cFLIP is sufficient to sensitize human melanoma cells to TRAIL‐ and CD95L‐mediated apoptosis. Oncogene 2008; 27:3211–3220. DOI:10.1038/sj.onc.1210985
45 - Balsas P, Lopez‐Royuela N, Galan‐Malo P, Anel A, Marzo I, Naval J. Cooperation between Apo2L/TRAIL and bortezomib in multiple myeloma apoptosis. Biochem Pharmacol 2009; 77:804–812. DOI:10.1016/j.bcp.2008.11.024
46 - Palacios C, Yerbes R, Lopez‐Rivas A. Flavopiridol induces cellular FLICE‐inhibitory protein degradation by the proteasome and promotes TRAIL‐induced early signaling and apoptosis in breast tumor cells. Cancer Res 2006; 66:8858–8869. DOI:10.1158/0008‐5472.CAN‐06‐0808
47 - Fulda S. Caspase‐8 in cancer biology and therapy. Cancer Lett 2009; 281:128–133. DOI:10.1016/j.canlet.2008.11.023
48 - Eggert A, Grotzer MA, Zuzak TJ, et al. Resistance to tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐induced apoptosis in neuroblastoma cells correlates with a loss of caspase‐8 expression. Cancer Res 2001; 61:1314–1319.
49 - Fulda S, Debatin KM. 5‐Aza‐2’‐deoxycytidine and IFN‐gamma cooperate to sensitize for TRAIL‐induced apoptosis by upregulating caspase‐8. Oncogene 2006; 25:5125–5133. DOI:10.1038/sj.onc.1209518
50 - Fulda S, Poremba C, Berwanger B, et al. Loss of caspase‐8 expression does not correlate with MYCN amplification, aggressive disease, or prognosis in neuroblastoma. Cancer Res 2006; 66:10016–10023. DOI:10.1158/0008‐5472.CAN‐05‐4079
51 - Teitz T, Wei T, Valentine MB, et al. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med 2000; 6:529–535. DOI:10.1038/75007
52 - Himeji D, Horiuchi T, Tsukamoto H, Hayashi K, Watanabe T, Harada M. Characterization of caspase‐8L: a novel isoform of caspase‐8 that behaves as an inhibitor of the caspase cascade. Blood 2002; 99:4070–4078. DOI:
53 - Miller MA, Karacay B, Zhu X, O'Dorisio MS, Sandler AD. Caspase 8L, a novel inhibitory isoform of caspase 8, is associated with undifferentiated neuroblastoma. Apoptosis 2006; 11:15–24. DOI:10.1007/s10495‐005‐3258‐0
54 - Cursi S, Rufini A, Stagni V, et al. Src kinase phosphorylates Caspase‐8 on Tyr380: a novel mechanism of apoptosis suppression. EMBO J 2006; 25:1895–1905. DOI:10.1038/sj.emboj.7601085
55 - Lin Y, Devin A, Cook A, et al. The death domain kinase RIP is essential for TRAIL (Apo2L)‐induced activation of IkappaB kinase and c‐Jun N‐terminal kinase. Mol Cell Biol 2000; 20:6638–6645. DOI: 10.1128/MCB.20.18.6638‐6645.2000
56 - Morel J, Audo R, Hahne M, Combe B. Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen‐activated protein kinases and phosphatidylinositol 3‐kinase/Akt. J Biol Chem 2005; 280:15709–15718. DOI:10.1074/jbc.M414469200
57 - Tran SE, Holmstrom TH, Ahonen M, Kahari VM, Eriksson JE. MAPK/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors. J Biol Chem 2001; 276:16484–16490. DOI:10.1074/jbc.M010384200
58 - Grunert M, Gottschalk K, Kapahnke J, Gundisch S, Kieser A, Jeremias I. The adaptor protein FADD and the initiator caspase‐8 mediate activation of NF‐kappaB by TRAIL. Cell Death Dis 2012; 3:e414. DOI:10.1038/cddis.2012.154
59 - Galluzzi L, Kepp O, Kroemer G. RIP kinases initiate programmed necrosis. J Mol Cell Biol 2009; 1:8–10. DOI:10.1093/jmcb/mjp007
60 - Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P. The death domain kinase RIP mediates the TNF‐induced NF‐kappaB signal. Immunity 1998; 8:297–303. DOI:10.1016/S1074‐7613(00)80535‐X
61 - Lin Y, Devin A, Rodriguez Y, Liu ZG. Cleavage of the death domain kinase RIP by caspase‐8 prompts TNF‐induced apoptosis. Genes Dev 1999; 13:2514–2526. DOI: 10.1101/gad.13.19.2514
62 - Cho YS, Challa S, Moquin D, et al. Phosphorylation‐driven assembly of the RIP1‐RIP3 complex regulates programmed necrosis and virus‐induced inflammation. Cell 2009; 137:1112–1123. DOI:10.1016/j.cell.2009.05.037
63 - Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ. Activation of IKK by TNFalpha requires site‐specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell 2006; 22:245–257. DOI:10.1016/j.molcel.2006.03.026
64 - Gerlach B, Cordier SM, Schmukle AC, et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 2011; 471:591–596. DOI:10.1038/nature09816
65 - He W, Wang Q, Xu J, et al. Attenuation of TNFSF10/TRAIL‐induced apoptosis by an autophagic survival pathway involving TRAF2‐ and RIPK1/RIP1‐mediated MAPK8/JNK activation. Autophagy 2012; 8:1811–1821. DOI:10.4161/auto.22145
66 - Hou W, Han J, Lu C, Goldstein LA, Rabinowich H. Autophagic degradation of active caspase‐8: a crosstalk mechanism between autophagy and apoptosis. Autophagy 2010; 6:891–900. DOI:10.4161/auto.6.7.13038
67 - Niu TK, Cheng Y, Ren X, Yang JM. Interaction of Beclin 1 with survivin regulates sensitivity of human glioma cells to TRAIL‐induced apoptosis. FEBS Lett 2010; 584:3519–3524. DOI:10.1016/j.febslet.2010.07.018
68 - Zhang Y, Zhang B. TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5. Mol Cancer Res 2008; 6:1861–1871. DOI:10.1158/1541‐7786.MCR‐08‐0313
69 - Han J, Hou W, Goldstein LA, et al. Involvement of protective autophagy in TRAIL resistance of apoptosis‐defective tumor cells. J Biol Chem 2008; 283:19665–19677. DOI:10.1074/jbc.M710169200
70 - Chiacchiera F, Grossi V, Cappellari M, et al. Blocking p38/ERK crosstalk affects colorectal cancer growth by inducing apoptosis in vitro and in preclinical mouse models. Cancer Lett 2012; 324:98–108. DOI:10.1016/j.canlet.2012.05.006
71 - Herrero‐Martin G, Hoyer‐Hansen M, Garcia‐Garcia C, et al. TAK1 activates AMPK‐dependent cytoprotective autophagy in TRAIL‐treated epithelial cells. EMBO J 2009; 28:677–685. DOI:10.1038/emboj.2009.8
72 - Han J, Hou W, Goldstein LA, Stolz DB, Watkins SC, Rabinowich H. A Complex between Atg7 and Caspase‐9: a novel mechanism of cross‐regulation between autophagy and apoptosis. J Biol Chem 2014; 289:6485–6497. DOI:10.1074/jbc.M113.536854
73 - Di X, Zhang G, Zhang Y, Takeda K, Rivera Rosado LA, Zhang B. Accumulation of autophagosomes in breast cancer cells induces TRAIL resistance through downregulation of surface expression of death receptors 4 and 5. Oncotarget 2013; 4:1349–1364. DOI:10.18632/oncotarget.1174
74 - Yao Z, Zhang P, Guo H, et al. RIP1 modulates death receptor mediated apoptosis and autophagy in macrophages. Mol Oncol 2015; 9:806–817. DOI:10.1016/j.molonc.2014.12.004
75 - Wang W, Zhou J, Shi J, et al. Human T‐cell leukemia virus type 1 Tax‐deregulated autophagy pathway and c‐FLIP expression contribute to resistance against death receptor‐mediated apoptosis. J Virol 2014; 88:2786–2798. DOI:10.1128/JVI.03025‐13