TRAIL Signaling Pathways: History
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Contributor:
Manjari Kundu
,
Yoshimi Endo Greer
,
Jennifer L. Dine
,
Stanley Lipkowitz

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein that undergoes proteolytic cleavage to produce an extracellular ligand. TRAIL can bind to decoy receptor 1 (DcR1) which lacks a death domain (DD) altogether, and DcR2 which has a truncated DD. These decoy receptors are unable to induce DISC (death-inducing signaling complex) formation and act as negative regulators of the apoptotic signaling by competitively binding TRAIL. The canonical TRAIL-induced apoptotic signaling pathway is an example of apoptosis mediated through the extrinsic death pathway, which entails activation of cell-surface receptors by a ligand to induce activation of downstream caspases.

  • TRAIL
  • death receptors
  • apoptosis
  • triple-negative breast cancer

1. Introduction

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) amplification and accounts for ~15% of breast cancer cases [1]. It has the worst prognosis of the major subtypes of breast cancer due in part to the absence of well-defined molecular targets [1]. TNBC responds to chemotherapy, but metastatic relapse of the treated early stage is frequent, and there are no curative therapies in the advanced stage [1]. While new targeted therapies (e.g., trophoblast antigen 2 [trop2]-targeted antibody-drug conjugates [ADCs]) and immune checkpoint inhibitors have significant activity for the treatment of TNBC [2][3][4][5][6], novel therapies are still needed for TNBC especially in the advanced setting.
TRAIL is a member of the tumor necrosis factor (TNF) family of ligands capable of initiating apoptosis through engagement of its death receptors. TRAIL binds to Death Receptor 4 (DR4), also known as TRAIL-R1/TNFRSF10A) and Death Receptor 5 (DR5, also known as, TRAIL-R2/TRICK-2/KILLER/TNFRSF10B), causing caspase-mediated apoptosis (Figure 1A) [7][8]. TRAIL is mainly expressed on the cell surface of immune cells eliciting programmed death of target cells and has been reported to induce apoptosis in a variety of cancer cell lines while sparing the normal cells [7][9][10][11][12]. However, there are some reports of TRAIL-induced apoptosis in normal cells, such as primary salivary epithelial cells [13], prostate epithelial cells [14][15] and primary human epithelial esophageal cells [16]. Preclinical animal studies supported the lack of overt toxicity of TRAIL to the normal tissues [7][17][18]. Therefore, targeting TRAIL/DR pathway offers an attractive approach to induce apoptosis in cancer cells. Early attempts to treat cancer using the TNF and Fas ligand (FasL) as DR agonists showed disappointing results due to lack of efficacy or prohibitive preclinical toxicity [7][17][18]. This has prompted investigation into the use of TRAIL or DR4/5 agonist antibodies in cancer therapy. TRAIL agonist induced regression of cancer xenografts in mice without affecting normal tissues, and human phase 1 studies have demonstrated that TRAIL agonists are safe and well tolerated in patients [7][17][18][19][20][21][22][23]. However, phase 2/3 clinical trials utilizing recombinant human (rh)TRAIL and agonistic antibodies directed at DR4/5, while well-tolerated, have not shown significant clinical efficacy [23][24][25].
Cells 11 03717 g001aCells 11 03717 g001b
Figure 1. TRAIL signaling pathway. (A) Apoptosis pathway. Activation of DR4 and DR5 by TRAIL induces the extrinsic apoptosis pathway (left). The intrinsic pathway (right) is activated by a variety of stimuli and leads to release of proapoptotic proteins from the mitochondria. The two pathways interact as caspase-8 activated by the DRs can cleave BID which then activates the intrinsic pathway, and conversely, caspase-3 can cleave and activate caspase-8 in a feedback loop, thus amplifying the apoptotic signal. (B) TRAIL-mediated NF-kB/MAPK pathways. Anti- or pro-survival mechanisms appear to be context dependent. (C) TRAIL-mediated necroptosis pathway. (D) Crosstalk between TRAIL pathway and autophagy. APAF1, Apoptotic protease activating factor 1; DD, death domain; DED, death effector domain; DISC, death-inducing signaling complex; FADD, Fas-associated death domain protein; FLIP (FLICE [FADD-like IL-1β-converting enzyme]-inhibitory protein); MOMP, mitochondrial outer membrane permeabilization; SMAC, second mitochondrial activator of caspases; XIAP, X-linked inhibitor of apoptosis. TRAF2, TNF receptor-associated factor 2; NEMO, NF-kappa-B essential modulator; TRADD, Tumor necrosis factor receptor type 1-associated DEATH domain protein; NF-κB, nuclear factor-κB; MAPK, mitogen-activated protein kinase; MLKL, mixed-lineage kinase domain-like protein; ATG, Autophagy-related protein; LC3, Microtubule-associated proteins 1A/1B light chain 3; IAP: inhibitor of apoptosis. Figures were created with BioRender.com (accessed on 8 November 2022).

2. TRAIL Signaling Pathways

Activation of TRAIL death receptors by their cognate ligands induces apoptosis but as will be described below, under certain circumstances, activation of the TRAIL death receptors can promote growth and in tumors induce metastasis or pro-tumorigenic immune effects. The canonical TRAIL-induced apoptotic signaling pathway is an example of apoptosis mediated through the extrinsic death pathway, which entails activation of cell-surface receptors by a ligand to induce activation of downstream caspases (Figure 1A) [26]. Activation of DR4 and DR5 by TRAIL promotes receptor clustering and formation of the DISC [27]. The adaptor protein, Fas-associated death domain protein (FADD), also contains a death domain (DD) which interacts with the DD of DR4/5 in a homotypic fashion [27]. FADD also contains a death effector domain (DED) which recruits pro-caspases-8 and -10 via a homotypic interaction with DED of the pro-caspases [27]. The forced proximity of the pro-caspases-8 and -10 at the DISC leads to auto-processing of the pro-caspases [27], resulting in an active tetramer of two large and small subunits [27]. This results in activation of downstream caspases such as caspase-3 or -7, ultimately inducing apoptosis. FLIP (FLICE [FADD-like IL-1β-converting enzyme]-inhibitory protein), a negative regulator of the TRAIL pathway, is structurally related to pro-caspases-8 and -10 with N-terminal DED domains, and a C-terminal caspase-like domain, but the catalytic cysteine is replaced by tyrosine, thus rendering it catalytically inactive [28]. FLIP may also be recruited to the DISC, prevent caspase-8 or caspase-10 from interacting with FADD, and thus attenuate the apoptotic signal [27][28].
In some cells, activated caspase-8 or -10 can cleave Bid, a pro-apoptotic BH3-only BCL-2 family protein, into truncated Bid (tBid), which translocate to the mitochondria and activates the intrinsic death pathway (Figure 1A) [29][30][31]. The BCL-2 protein family regulates the intrinsic death pathway via anti- and pro-apoptotic family members [30]. When the intrinsic death pathway is activated, pro-apoptotic BCL-2 family members, such as BAD, BIM, and PUMA, antagonize anti-apoptotic family members, including BCL-2, BCL-xL, BCL-w, and MCL1 [30][32]. tBid directly and indirectly activates pro-apoptotic proteins Bak and Bax, causing mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release [29][30][33][34]. The scaffold protein apoptotic protease-activating factor 1 (APAF1) binds to cytochrome c and activates caspase-9 [29][30]. Second mitochondrial activator of caspases (SMAC), an inhibitor of apoptosis proteins (IAPs) that suppress caspase function, is also released during MOMP to help facilitate apoptosis [35]. The extrinsic and intrinsic death pathways converge; caspases-8, -10, and -9 mediate proteolytic processing of the executioner caspases-3 and -7 which carry out the final steps of apoptosis by cleaving numerous substrates [29][30]. Activated caspase-3 is also able to activate caspase-8 in a feedback-loop, thus amplifying the apoptotic signal [36][37].
Like TNF, TRAIL-induced DR4/5 activation has also been associated with the induction of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling [28][38][39][40] (Figure 1B). TNF signaling is a more potent activator of these pathways than TRAIL [39]. After TRAIL-induced caspase activation, receptor-interacting serine/threonine-protein kinase 1 (RIPK1/RIP1), FADD, TNF receptor-associated factor 2 (TRAF2), and caspase-8 form a secondary complex that facilitates kinase signaling in a RIPK1-dependent manner [39]. However, findings have been mixed concerning the anti- and pro-survival mechanisms induced by TRAIL-mediated NF-κB and MAPK activation [41][42]. Inhibition of components of the NF-κB and MAPK signaling pathways has produced examples of both enhanced and attenuated sensitivity to TRAIL-induced apoptosis, demonstrating that the outcomes associated with TRAIL-mediated activation of NF-κB and MAPK will vary depending on context and requires further characterization [41][42].
TRAIL signaling is also associated with non-apoptotic cell death mechanisms, including the caspase-independent, cell-regulated form of necrosis, necroptosis [42][43][44][45][46] (Figure 1C). TRAIL has been found to induce necroptosis regulators RIPK1 and RIPK3 in an acidic pH-dependent manner, and NF-κB inhibition has been found to enhance sensitivity to TRAIL-induced necroptosis [42][43][45][46]. Mechanistically, necroptosis depends on activation of RIPK1 and RIPK3 and necrosome complex formation involving RIPK1 and RIPK3 and the mixed lineage kinase domain-like protein (MLKL) [47] (Figure 1C). Recently, a study indicated the involvement of an E3 ubiquitin-protein ligase TRIM21(tripartite motif containing 21) in endogenous TRAIL-mediated necrosome formation [48]. Further elucidation of the mechanisms and conditions under which TRAIL activates necroptotic signaling is needed.
Importantly, numerous studies show that TRAIL can also induce autophagy [49]. Autophagy and apoptosis are both important cellular processes controlled by distinct groups of regulatory mechanisms [50]. They also have a crosstalk to regulate each other [51][52][53]. As shown in Figure 1D, autophagy and apoptosis share same regulatory factors, including the Bcl-2 family [30][52][54] and FLIP [55]. Bcl-2 family members inhibit Beclin-1 [56][57] which is required for activation of autophagy [58]. FLIP limits the ATG3-mediated LC3 conjugation to inhibit autophagosome biogenesis [55]. Caspase-8 has been shown to regulate autophagy by targeting autophagic components, such as ATG3, ATG5 and Beclin-1 [59][60][61][62]. Autophagosome formation can facilitate caspase-8 activation by providing a platform consisting of ATG5 and LC3 in some contexts [63], while sequestration of pro-caspase-8 to the autophagosome can lead to either caspase-8 induction, or downregulation [64]. The importance of autophagy in TRAIL resistance breast cancer cells is still being studied intensively. Notably, in different models of breast cancer cell lines resistance to TRAIL-induced killing was attributed by TRAIL induced autophagy [65]. Furthermore, in a series of breast cancer cell lines autophagy was shown to have an impact on dynamics of TRAIL receptors. In these cell lines, autophagosome accumulation led to decrease in TRAIL-induced death by downregulating the TRAIL receptors [66]. While these data suggest that TRAIL-induced autophagy inhibits TRAIL-mediated death, there are descriptions of TRAIL-induced autophagic cell death. For example, in a 3D culture model of breast lumen formation using the immortalized but not transformed human mammary MCF-10A cell line, TRAIL-induced autophagy contributed to the death of the luminal cells that led to hollow lumen formation [67]. Thus, understanding TRAIL-induced autophagy is required to decipher TRAIL mediated response or resistance.
TRAIL and DR expression have been shown to positively regulate cell growth under certain conditions. Specifically, TRAIL signaling promotes proliferation and IFNγ production in pre-activated T cells [68]. TRAIL-induced activation of DR5 and mTRAIL-R signaling is correlated with enhanced TNBC-associated bone metastasis and KRAS-driven lung and pancreatic cancer metastasis, respectively [69][70]. The first study utilized a bone tropic variant of the TNBC MDA-MB-231 cell line which is known to contain an oncogenic KRAS mutation which is infrequent in breast cancer [71]. In their study the investigators found that DR5 was upregulated in the bone tropic cells compared to the parental MDA-MB-231 cell line and they demonstrate that RNAi mediated knockdown of DR5 reduces the levels of bone metastasis related genes (e.g., HMGA2, phosphor-Src, and the C-X-C cytokine receptor 4) in the cancer cell. When injected intracardially, the knockdown of DR5 reduced the ability of the cells to metastasize to bone [69]. Thus, the pro-metastatic phenotypes were reversed with DR5 and mTRAIL-R inhibition, suggesting that inhibition of the TRAIL signaling may provide a novel method to inhibit metastasis.
As discussed above, TRAIL knockout mice have shown increased metastases [72]. Additional characterization of the conditions under which TRAIL signaling is inhibitory or pro-proliferative or pro-metastatic is necessary to determine the contexts wherein TRAIL pathway activation or inhibition are the appropriate therapeutic strategy in TNBC.

This entry is adapted from the peer-reviewed paper 10.3390/cells11233717

References

  1. Sharma, P. Biology and Management of Patients with Triple-Negative Breast Cancer. Oncologist 2016, 21, 1050–1062.
  2. Bardia, A.; Hurvitz, S.A.; Rugo, H.S. Sacituzumab Govitecan in Metastatic Breast Cancer. Reply. N. Engl. J. Med. 2021, 385, e12.
  3. Cortes, J.; Cescon, D.W.; Rugo, H.S.; Nowecki, Z.; Im, S.-A.; Yusof, M.M.; Gallardo, C.; Lipatov, O.; Barrios, C.H.; Holgado, E.; et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020, 396, 1817–1828.
  4. Cortes, J.; Rugo, H.S.; Cescon, D.W.; Im, S.-A.; Yusof, M.M.; Gallardo, C.; Lipatov, O.; Barrios, C.H.; Perez-Garcia, J.; Iwata, H.; et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N. Engl. J. Med. 2022, 387, 217–226.
  5. Schmid, P.; Adams, S.; Rugo, H.S.; Schneeweiss, A.; Barrios, C.H.; Iwata, H.; Diéras, V.; Hegg, R.; Im, S.-A.; Shaw Wright, G.; et al. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N. Engl. J. Med. 2018, 379, 2108–2121.
  6. Schmid, P.; Cortes, J.; Dent, R.; Pusztai, L.; McArthur, H.; Kümmel, S.; Bergh, J.; Denkert, C.; Park, Y.H.; Hui, R.; et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N. Engl. J. Med. 2022, 386, 556–567.
  7. Ashkenazi, A.; Dixit, V.M. Apoptosis control by death and decoy receptors. Curr. Opin. Cell Biol. 1999, 11, 255–260.
  8. Griffith, T.S.; Lynch, D.H. TRAIL: A molecule with multiple receptors and control mechanisms. Curr. Opin. Immunol. 1998, 10, 559–563.
  9. Jeremias, I.; Herr, I.; Boehler, T.; Debatin, K.M. TRAIL/Apo-2-ligand-induced apoptosis in human T cells. Eur. J. Immunol. 1998, 28, 143–152.
  10. Pan, G.; O’Rourke, K.; Chinnaiyan, A.M.; Gentz, R.; Ebner, R.; Ni, J.; Dixit, V.M. The receptor for the cytotoxic ligand TRAIL. Science 1997, 276, 111–113.
  11. Marsters, S.; Sheridan, J.; Pitti, R.; Huang, A.; Skubatch, M.; Baldwin, D.; Yuan, J.; Gurney, A.; Goddard, A.; Godowski, P.; et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr. Biol. 1997, 7, 1003–1006.
  12. Wiley, S.R.; Schooley, K.; Smolak, P.J.; Din, W.S.; Huang, C.-P.; Nicholl, J.K.; Sutherland, G.R.; Smith, T.D.; Rauch, C.; Smith, C.A.; et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995, 3, 673–682.
  13. Nakamura, H.; Kawakami, A.; Iwamoto, N.; Ida, H.; Koji, T.; Eguchi, K. Rapid and significant induction of TRAIL-mediated type II cells in apoptosis of primary salivary epithelial cells in primary Sjögren’s syndrome. Apoptosis 2008, 13, 1322–1330.
  14. Nesterov, A.; Ivashchenko, Y.; Kraft, A.S. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in normal prostate epithelial cells. Oncogene 2002, 21, 1135–1140.
  15. Thorburn, J.; Moore, F.; Rao, A.; Barclay, W.W.; Thomas, L.R.; Grant, K.W.; Cramer, S.D.; Thorburn, A. Selective Inactivation of a Fas-associated Death Domain Protein (FADD)-dependent Apoptosis and Autophagy Pathway in Immortal Epithelial Cells. Mol. Biol. Cell 2005, 16, 1189–1199.
  16. Kim, S.-H.; Kim, K.; Kwagh, J.G.; Dicker, D.T.; Herlyn, M.; Rustgi, A.K.; Chen, Y.; El-Deiry, W.; Kim, S.-H.; Kim, K.; et al. Death Induction by Recombinant Native TRAIL and Its Prevention by a Caspase 9 Inhibitor in Primary Human Esophageal Epithelial Cells. J. Biol. Chem. 2004, 279, 40044–40052.
  17. Walczak, H.; Miller, R.E.; Ariail, K.; Gliniak, B.; Griffith, T.S.; Kubin, M.; Chin, W.; Jones, J.; Woodward, A.; Le, T.; et al. Tu-moricidal activity of tumor necrosis factor-related apoptosis- inducing ligand in vivo. Nat. Med. 1999, 5, 157–163.
  18. Yerbes, R.; Palacios, C.; López-Rivas, A. The therapeutic potential of TRAIL receptor signalling in cancer cells. Clin. Transl. Oncol. 2011, 13, 839–847.
  19. Camidge, D.R.; Herbst, R.S.; Gordon, M.S.; Eckhardt, S.G.; Kurzrock, R.; Durbin, B.; Ing, J.; Tohnya, T.M.; Sager, J.; Ashkenazi, A.; et al. A Phase I Safety and Pharmacokinetic Study of the Death Receptor 5 Agonistic Antibody PRO95780 in Patients with Advanced Malignancies. Clin. Cancer Res. 2010, 16, 1256–1263.
  20. Doi, T.; Murakami, H.; Ohtsu, A.; Fuse, N.; Yoshino, T.; Yamamoto, N.; Boku, N.; Onozawa, Y.; Hsu, C.-P.; Gorski, K.S.; et al. Phase 1 study of conatumumab, a pro-apoptotic death receptor 5 agonist antibody, in Japanese patients with advanced solid tumors. Cancer Chemother. Pharmacol. 2010, 68, 733–741.
  21. Forero-Torres, A.; Shah, J.; Wood, T.; Posey, J.; Carlisle, R.; Copigneaux, C.; Luo, F.; Wojtowicz-Praga, S.; Percent, I.; Saleh, M. Phase I Trial of Weekly Tigatuzumab, an Agonistic Humanized Monoclonal Antibody Targeting Death Receptor 5 (DR5). Cancer Biother. Radiopharm. 2010, 25, 13–19.
  22. Soria, J.-C.; Márk, Z.; Zatloukal, P.; Szima, B.; Albert, I.; Juhász, E.; Pujol, J.-L.; Kozielski, J.; Baker, N.; Smethurst, D.; et al. Randomized Phase II Study of Dulanermin in Combination with Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non–Small-Cell Lung Cancer. J. Clin. Oncol. 2011, 29, 4442–4451.
  23. Younes, A.; Vose, J.M.; Zelenetz, A.D.; Smith, M.R.; Burris, H.A.; Ansell, S.M.; Klein, J.; Halpern, W.; Miceli, R.; Kumm, E.; et al. A Phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin’s lymphoma. Br. J. Cancer 2010, 103, 1783–1787.
  24. Ouyang, X.; Shi, M.; Jie, F.; Bai, Y.; Shen, P.; Yu, Z.; Wang, X.; Huang, C.; Tao, M.; Wang, Z.; et al. Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer. Investig. New Drugs 2017, 36, 315–322.
  25. Micheau, O.; Shirley, S.; Dufour, F. Death receptors as targets in cancer. J. Cereb. Blood Flow Metab. 2013, 169, 1723–1744.
  26. Rahman, M.; Davis, S.R.; Pumphrey, J.G.; Bao, J.; Nau, M.M.; Meltzer, P.S.; Lipkowitz, S. TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype. Breast Cancer Res. Treat. 2009, 113, 217–230.
  27. Ashkenazi, A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat. Rev. Cancer 2002, 2, 420–430.
  28. Irmler, M.; Thome, M.; Hahne, M.; Schneider, P.; Hofmann, K.; Steiner, V.; Bodmer, J.-L.; Schröter, M.; Burns, K.; Mattmann, C.; et al. Inhibition of Death Receptor Signals by Cellular FLIP. Nature 1997, 388, 190–195.
  29. Danial, N.N.; Korsmeyer, S.J. Cell Death: Critical Control Points. Cell 2004, 116, 205–219.
  30. Czabotar, P.E.; Lessene, G.; Strasser, A.; Adams, J.M. Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 2014, 15, 49–63.
  31. Li, H.; Zhu, H.; Xu, C.J.; Yuan, J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998, 94, 491–501.
  32. Cragg, M.S.; Harris, C.; Strasser, A.; Scott, C.L. Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics. Nat. Rev. Cancer 2009, 9, 321–326.
  33. Emery, J.G.; McDonnell, P.; Burke, M.B.; Deen, K.C.; Lyn, S.; Silverman, C.; Dul, E.; Appelbaum, E.R.; Eichman, C.; DiPrinzio, R.; et al. Osteoprotegerin Is a Receptor for the Cytotoxic Ligand TRAIL. J. Biol. Chem. 1998, 273, 14363–14367.
  34. Westphal, D.; Dewson, G.; Czabotar, P.E.; Kluck, R.M. Molecular biology of Bax and Bak activation and action. Biochim. Biophys. Acta BBA Bioenerg. 2011, 1813, 521–531.
  35. Du, C.; Fang, M.; Li, Y.; Li, L.; Wang, X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase acti-vation by eliminating IAP inhibition. Cell 2000, 102, 33–42.
  36. Slee, E.A.; Harte, M.T.; Kluck, R.M.; Wolf, B.B.; Casiano, C.A.; Newmeyer, D.D.; Wang, H.G.; Reed, J.C.; Nicholson, D.W.; Alnemri, E.S.; et al. Ordering the cytochrome c-initiated caspase cascade: Hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J. Cell Biol. 1999, 144, 281–292.
  37. Garimella, S.V.; Gehlhaus, K.; Dine, J.L.; Pitt, J.J.; Grandin, M.; Chakka, S.; Nau, M.M.; Caplen, N.J.; Lipkowitz, S. Identification of novel molecular regulators of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in breast cancer cells by RNAi screening. Breast Cancer Res. 2014, 16, R41.
  38. Chaudhary, P.M.; 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.
  39. Varfolomeev, E.; Maecker, H.; Sharp, D.; Lawrence, D.; Renz, M.; Vucic, D.; Ashkenazi, A. Molecular Determinants of Kinase Pathway Activation by Apo2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand. J. Biol. Chem. 2005, 280, 40599–40608.
  40. Keane, M.M.; Rubinstein, Y.; Cuello, M.; Ettenberg, S.A.; Banerjee, P.; Nau, M.M.; Lipkowitz, S. Inhibition of NF-kappaB ac-tivity enhances TRAIL mediated apoptosis in breast cancer cell lines. Breast Cancer Res. Treat. 2000, 64, 211–219.
  41. Graves, J.D.; Kordich, J.J.; Huang, T.-H.; Piasecki, J.; Bush, T.L.; Sullivan, T.; Foltz, I.N.; Chang, W.; Douangpanya, H.; Dang, T.; et al. Apo2L/TRAIL and the Death Receptor 5 Agonist Antibody AMG 655 Cooperate to Promote Receptor Clustering and Antitumor Activity. Cancer Cell 2014, 26, 177–189.
  42. Azijli, K.; Weyhenmeyer, B.; Peters, G.J.; De Jong, S.; Kruyt, F.A.E. Non-canonical kinase signaling by the death ligand TRAIL in cancer cells: Discord in the death receptor family. Cell Death Differ. 2013, 20, 858–868.
  43. Jouan-Lanhouet, S.; Arshad, M.I.; Piquet-Pellorce, C.; Martin-Chouly, C.; Le Moigne-Muller, G.; Van Herreweghe, F.; Takahashi, N.; Sergent, O.; Lagadic-Gossmann, D.; Vandenabeele, P.; et al. TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. Cell Death Differ. 2012, 19, 2003–2014.
  44. Kemp, T.J.; Kim, J.-S.; Crist, S.A.; Griffith, T.S. Induction of necrotic tumor cell death by TRAIL/Apo-2L. Apoptosis 2003, 8, 587–599.
  45. Meurette, O.; Huc, L.; Rebillard, A.; Le Moigne, G.; Lagadic-Gossmann, D.; Dimanche-Boitrel, M.-T. TRAIL (TNF-Related Apoptosis-Inducing Ligand) Induces Necrosis-Like Cell Death in Tumor Cells at Acidic Extracellular pH. Ann. N. Y. Acad. Sci. 2005, 1056, 379–387.
  46. Meurette, O.; Rebillard, A.; Huc, L.; Le Moigne, G.; Merino, D.; Micheau, O.; Lagadic-Gossmann, D.; Dimanche-Boitrel, M.-T. TRAIL Induces Receptor-Interacting Protein 1–Dependent and Caspase-Dependent Necrosis-Like Cell Death under Acidic Extracellular Conditions. Cancer Res. 2007, 67, 218–226.
  47. Mandal, R.; Barrón, J.C.; Kostova, I.; Becker, S.; Strebhardt, K. Caspase-8: The double-edged sword. Biochim. Biophys. Acta (BBA)-Rev. Cancer 2020, 1873, 188357.
  48. Eugénio, M.S.; Faurez, F.; Kara-Ali, G.H.; Lagarrigue, M.; Uhart, P.; Bonnet, M.C.; Gallais, I.; Com, E.; Pineau, C.; Samson, M.; et al. TRIM21, a New Component of the TRAIL-Induced Endogenous Necrosome Complex. Front. Mol. Biosci. 2021, 8, 645134.
  49. Sharma, A.; Almasan, A. Autophagy as a mechanism of Apo2L/TRAIL resistance. Cancer Biol. Ther. 2018, 19, 755–762.
  50. Eisenberg-Lerner, A.; Bialik, S.; Simon, H.-U.; Kimchi, A. Life and death partners: Apoptosis, autophagy and the cross-talk between them. Cell Death Differ. 2009, 16, 966–975.
  51. Mukhopadhyay, S.; Panda, P.K.; Sinha, N.; Das, D.N.; Bhutia, S.K. Autophagy and apoptosis: Where do they meet? Apoptosis 2014, 19, 555–566.
  52. Nikoletopoulou, V.; Markaki, M.; Palikaras, K.; Tavernarakis, N. Crosstalk between apoptosis, necrosis and autophagy. Biochim. Biophys. Acta 2013, 1833, 3448–3459.
  53. Booth, L.A.; Tavallai, S.; Hamed, H.A.; Cruickshanks, N.; Dent, P. The role of cell signalling in the crosstalk between autophagy and apoptosis. Cell. Signal. 2013, 26, 549–555.
  54. Zhou, F.; Yang, Y.; Xing, D. Bcl-2 and Bcl-xL play important roles in the crosstalk between autophagy and apoptosis. FEBS J. 2010, 278, 403–413.
  55. Lee, J.-S.; Li, Q.; Lee, J.-Y.; Lee, S.-H.; Jeong, J.H.; Lee, H.-R.; Chang, H.; Zhou, F.-C.; Gao, S.-J.; Liang, C.; et al. FLIP-mediated autophagy regulation in cell death control. Nat. Cell Biol. 2009, 11, 1355–1362.
  56. Oberstein, A.; Jeffrey, P.D.; Shi, Y. Crystal Structure of the Bcl-XL-Beclin 1 Peptide Complex: Beclin 1 is a novel BH3-only protein. J. Biol. Chem. 2007, 282, 13123–13132.
  57. Liang, X.H.; Kleeman, L.K.; Jiang, H.H.; Gordon, G.; Goldman, J.E.; Berry, G.; Herman, B.; Levine, B. Protection against Fatal Sindbis Virus Encephalitis by Beclin, a Novel Bcl-2-Interacting Protein. J. Virol. 1998, 72, 8586–8596.
  58. Green, D.R.; Levine, B. To Be or Not to Be? How Selective Autophagy and Cell Death Govern Cell Fate. Cell 2014, 157, 65–75.
  59. Bell, B.D.; Leverrier, S.; Weist, B.M.; Newton, R.H.; Arechiga, A.F.; Luhrs, K.A.; Morrissette, N.S.; Walsh, C.M. FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells. Proc. Natl. Acad. Sci. USA 2008, 105, 16677–16682.
  60. You, M.; Savaraj, N.; Kuo, M.T.; Wangpaichitr, M.; Varona-Santos, J.; Wu, C.; Nguyen, D.M.; Feun, L. TRAIL induces autophagic protein cleavage through caspase activation in melanoma cell lines under arginine deprivation. Mol. Cell. Biochem. 2012, 374, 181–190.
  61. Wirawan, E.; Vande Walle, L.; Kersse, K.; Cornelis, S.; Claerhout, S.; Vanoverberghe, I.; Roelandt, R.; De Rycke, R.; Verspurten, J.; Declercq, W.; et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis. 2010, 1, e18.
  62. Oral, O.; Oz-Arslan, D.; Itah, Z.; Naghavi, A.; Deveci, R.; Karacali, S.; Gozuacik, D. Cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death. Apoptosis 2012, 17, 810–820.
  63. Senn, M.; Langhans, W.; Scharrer, E. Meal patterns of pygmy goats fed hay and concentrate ad lib. Physiol. Behav. 1990, 48, 49–53.
  64. Tsapras, P.; Nezis, I.P. Caspase involvement in autophagy. Cell Death Differ. 2017, 24, 1369–1379.
  65. Hou, W.; Han, J.; Lu, C.; Goldstein, L.A.; Rabinowich, H. Autophagic degradation of active caspase-8: A crosstalk mechanism between autophagy and apoptosis. Autophagy 2010, 6, 891–900.
  66. Di, X.; Zhang, G.; Zhang, Y.; Takeda, K.; Rivera Rosado, L.A.; 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.
  67. Mills, K.R.; Reginato, M.; Debnath, J.; Queenan, B.; Brugge, J.S. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc. Natl. Acad. Sci. USA 2004, 101, 3438–3443.
  68. Chou, A.H.; Tsai, H.F.; Lin, L.L.; Hsieh, S.L.; Hsu, P.I.; Hsu, P.N. Enhanced proliferation and increased IFN-gamma produc-tion in T cells by signal transduced through TNF-related apoptosis-inducing ligand. J. Immunol. 2001, 167, 1347–1352.
  69. Fritsche, H.; Heilmann, T.; Tower, R.J.; Hauser, C.; Von Au, A.; El-Sheikh, D.; Campbell, G.M.; Alp, G.; Schewe, D.; Hübner, S.; et al. TRAIL-R2 promotes skeletal metastasis in a breast cancer xenograft mouse model. Oncotarget 2015, 6, 9502–9516.
  70. von Karstedt, S.; Conti, A.; Nobis, M.; Montinaro, A.; Hartwig, T.; Lemke, J.; Legler, K.; Annewanter, F.; Campbell, A.D.; Taraborrelli, L.; et al. Cancer Cell-Autonomous TRAIL-R Signaling Promotes KRAS-Driven Cancer Progression, Invasion, and Metastasis. Cancer Cell 2015, 27, 561–573.
  71. Hollestelle, A.; Nagel, J.H.A.; Smid, M.; Lam, S.; Elstrodt, F.; Wasielewski, M.; Ng, S.S.; French, P.; Peeters, J.K.; Rozendaal, M.J.; et al. Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res. Treat. 2009, 121, 53–64.
  72. Cretney, E.; Takeda, K.; Yagita, H.; Glaccum, M.; Peschon, J.J.; Smyth, M.J. Increased Susceptibility to Tumor Initiation and Metastasis in TNF-Related Apoptosis-Inducing Ligand-Deficient Mice. J. Immunol. 2002, 168, 1356–1361.
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