TRAIL, Fas Ligand, TNF and TLR3 in Cancer, Resistance to Targeted Anti-Cancer Therapeutics, DOI 10.1007/978-3-319-56805-8 310 Index

Index

A Apoptosis Acid sphingomyelinase (aSMase), 230, 231, aberrant regulation, 81–82 233, 234, 236, 240 anti-tumor assay, 135 Activation-induced cell death (AICD), CD95 antagonists, 134 144–145 cIAP-1- and cIAP-2-molecular Acute lymphoblastic leukemia (ALL), 67 mechanism, 135 Acute respiratory distress syndrome clinical trials, 135 (ARDS), 139 control of, 80–81 Adoptive cell transfer (ACT), 145 cytochrome c and ATP, 134 Agonistic TRAIL-R2 antibody DR superfamily, 134 Drozitumab, 69 Krammer’s laboratory, 135 Ag-presenting cells (APCs) mitochondrion, 134 CD4+ Th cells, 132 non-apoptotic functions, 134 CD8+ cytotoxic lymphocytes, 132 non-apoptotic signalling Lpr and gld mice, 133 pathways, 135 MHC class II molecules, 131 PI3K signalling pathway, 135 non-self-Ags, 131 signalling pathways, 134 T-cell extravasation, 132 Apoptosome, 134 T-cells, 132 Apoptotic signalling, Fas/CD95 Th subset lineages, 132 CD74, 195–196 Aliphatic amino alcohol sphingoid c-FLIP, 191, 192 backbone, 230 chemotherapy and cancer 17-Allylamino-17-demethoxygeldanamycin anti-cancer drugs, 204–206 (17-AAG), 119 caspase-8, 207 ALPS. See Autoimmune lymphoproliferative cisplatin, 204 syndrome (ALPS) death receptors, 204 Amphipathic α helices, 257 edelfosine, 204, 207, 208 Anti-apoptosis antigen 1 (APO-1), 135 death receptor, 191 Antiapoptotic Bcl-2 proteins, 80, 83, 84 FAIM, 194 Anti-apoptotic factor BclxL, 144 FAP-1, 192–193 Anti-CD95 antibodies, 67 lipid rafts (see Lipid rafts, Fas/CD95) Anti-CD95-induced ceramide, 235 nucleolin, 194–195 Anti-CD95L antibodies, 137 proteins and signalling pathways, 192 Anti-ceramide antibodies, 233 Arginine N-GlcNAcylation, 266 Anti-GRP-78 antibody, 100 Arylquin-1, 103

Autoimmune lymphoproliferative syndrome Ceramide synthases (CerS), 230, 237 (ALPS), 140, 142, 145, 188 Ceramide-1-phosphate (C1P), 231 Autoimmunity, 137, 144 Ceramide-enriched membrane domains, 233 Autoinflammatory, 248 c-FLIP. See Cellular FADD-like Azadeoxycytidine, 98 interleukin-1β–converting enzyme (FLICE)-inhibitory protein (c-FLIP) Chemosensitivity, 93 B Cholangiocarcinoma (CCA), 119 B and T lymphocyte attenuator (BTLA), 255 Chronic lymphocytic leukemia (CLL), 68, 113 Baculoviral IAP repeat (BIR), 60 c-IAP1/2–RIPK1–NFκb signalling pathway, 143 BIR1-dependent interaction, 61 c-jun amino-terminal kinase (JNK), 62 and BIR3 domains, 60 cl-CD95L-induced S1P production, 239 XIAP, 61 cl-CD95L-induced Th17 endothelial Bax multimerization, 296 transmigration, 239 B-cells, 145 Cluster of apoptotic signalling molecule- Bcl-2 inhibitor HA14-1, 118 enriched rafts (CASMER), Bcl-2 protein, 64–65 197–199, 208 Blastocyst, 109 CRDs. See Cysteine-rich domains (CRDs) Boyden chamber assay, 237 c-src proto-oncogene, 97 BRAF inhibitors, 80 C-terminal leucine zipper domain, 93 Brefeldin-A (BFA), 98–100, 103 C-terminal nuclear export sequence, 93 Bronchoalveolar lavage (BAL), 139 Cycloheximide (CHX), 295, 297, 298, 304 Bruton’s tyrosine kinase (Btk), 113 Cysteine-rich domains (CRDs), 30, 40, 42 type I transmembrane proteins, 29 type II transmembrane proteins, 28 C Cytochrome c, 80, 295 Cancer, 59 Cytokine IAPs (see Inhibitors of apoptosis (IAPs)) and APCs, 132 Cancer stem cells (CSCs), 111 and chemokines, 143 Carcinogenesis ectodomain, 137 and chronic inflammatory disorders, 134 IL-1β and IL-18, 143 wild-type CD95 allele, 140 MCP-1 and IL-8, 135 CASMER. See Cluster of apoptotic signalling proinflammatory, 144 molecule-enriched rafts (CASMER) sTNF-α, 136 Caspase Recruitment Domain (CARD), 62 T-cells, 132 Caspase-9-deficient Jurkat cells, 235 Cytoplasmic tail, 136 CD34+ stem cells, 113 Cytosolic cytochrome c, 66 CD4+ helper T-cells, 132 Cytotoxic T-lymphocytes, 80 CD95–CD95L interaction, 140 CD95–CD95L pair, 132, 133, 139, 142, 145 CD95-DD:FADD-DD crystal structure, 141 D CD95-mediated cell apoptosis Dabrafenib, 82 ceramide and caspases, 235 Damage-associated molecular patterns in lipid rafts, 232–234 (DAMPs), 32, 33 sphingolipids, 235–239 Death induced by CD95R/L elimination Cell signalling pathways (DICE), 143 CD95 and CD95L, 141–142 Death inducing signalling complex (DISC) CD95L, 137–140 apoptosis, 202, 207 Cell therapy, 108 caspase-8 activation, 199 Cellular FADD-like interleukin-1β–converting c-FLIP, 191 enzyme (FLICE)-inhibitory protein FADD and procaspase-8, 190 (c-FLIP), 191, 194, 199, 208 visualization, lipid raft platform, 197–199 Cellular inhibitor of apoptosis proteins Death receptors (DR), 98–101, 188–190 (cIAPs), 80, 81 ABT-737, 118 Index 311

activation of, 108 TLR3 expression anti-apoptotic Bcl-2 family, 240 autocrine IFN-β, 163 anti-tumour agent, 116 monocyte-derived DC (mDC), 161 apoptotic signalling, 240 nucleotide-sensing TLRs, 162 Bortezombib, 117 phosphorylation, 163 clinical trial, 115 primary human epithelial cells, 161 cytotoxicity, 39 primary mouse β-pancreatic cells, 163 downregulation of TRAIL-R1 and RHIM, 163 TRAIL-R2, 40 signaling pathways, 162 DR4 and DR5 clusters, 240 TLR3 gene and protein, 160–161 dulanermin, 39 viral protection, 164 Fas/CD95 DR-signalling, 63 “death domain” (DD), 188 dsRNAs. See Double-stranded RNAs amino acids, 188, 189 (dsRNAs) apoptosis, 190 Dysplasias, 248 dysregulation and mutations, 190 FADD, 189 protein–protein interaction, 189 E regulatory factors, 190 E3-ubiquitin ligase, 61, 62 HSCs and ESCs, 119–120 EGF receptor (EGFR), 237 hyperthermic-isolated limb perfusion, 115 Enteropathogenic Escherichia coli (EPEC), 266 ligand-mediated biological mechanisms, 108 Epidermal growth factor receptor (EGFR), 162 LIGHT, 115 Epithelial–mesenchymal transition (EMT), 238 mapatumumab and lexatumumab, 39 Mcl-1 and cIAP2, 119 MSC-TRAIL, 116 F PKB/Akt, 119 FADD recruitment, 142 polyethylene glycol, 39 Fanconi anaemia, 113 single-chain TRAIL (scTRAIL), 39 FAP-1. See Fas-associated phosphatase-1 single-chain variable fragment (scFv) (FAP-1) domains, 39 Fas activity, 95, 98, 99 stem cell-based treatments, 119 Fas apoptosis inhibitory molecule (FAIM), 194 sTRAIL, 116 Fas-associated death domain protein (FADD), synergise with TRAIL, 117 2, 4, 8, 9, 12, 13, 32, 33, 64, 134, TNF, 115 136, 137, 141, 142, 189, 197, 198, tumour immune therapies, 115 201, 207, 233, 234, 237 XIAP, 118, 119 Fas-associated phosphatase-1 (FAP-1), 192–193 Death- vs. motility-ISCs, 140 Fas/CD95 Death-Effector-Domain (DED), 261 ALPS, 188 Death-inducing signalling complex (DISC), 2, 7, apoptosis (see Apoptotic signalling, 8, 10, 12, 13, 95, 98–100, 108, 257, Fas/CD95) 258, 261, 265, 267, 294, 295, 305 ceramide and lipid rafts, 199–201 Dendritic cells (DC), 144 death receptor and apoptosis, 188–190 Diacylglycerol (DAG), 230 lymphocytes, 187 Dihydroceramide (dhCer), 230 non-apoptotic signalling, 190–191, 209 Dihydrosphingosine (sphinganine), 230 T cells, 188 Direct finite-time Lyapunov exponent (DLE), 300 FAS/FASL-induced apoptosis, 112 DISC. See Death-inducing signalling complex FasL- and TRAIL-induced apoptosis, 258 (DISC) FASL neutralising antibodies, 110 Disintegrin, 261 FASL/FAS system, 112 Docosahexaenoic acid (DHA), 240 Fas palmitoylation, 265 Double-stranded RNAs (dsRNAs), 161–163 Fas sialylation, 267 pathogens, 164 Follicular B helper T-cells, 145 self-RNAs, 164, 165 Follicular T-helper cells (TFH), 132 312 Index

FTY720-based therapy, 241 Immune cells Fucosylation, 267, 268 CD95L, 143–144 Immune-deficient nude mice, 115 Importin β1, 7 G Induced MSCs (iMSCs), 120 Galactosylceramide (GalCer), 230 Inflammation, 133, 136, 137, 146, 147 Galactosylceramide synthase (GalCerS), 230 Inhibitors of apoptosis (IAPs), 9, 10, 66–67 Galectins, 269 anti-apoptotic activity, 60 Gastric tumour xenograft mouse model, 115 baculoviruses, 59 GDP-mannose-4,6-dehydratase (GMDS), 267 DR-induced apoptosis, 64–66 Generalized lymphoproliferative disease (gld), DR signalling pathways, 60 133, 142 human members, 59 Germinal center rogue cells (GCrs), 145 RIPK-dependent signalling complex, 62–64 GlcCer synthesis, 235 Smac mimetics (see Smac mimetics) GlcNAcylation, 266 structure and molecular functions, 60–62 Glioblastoma model, 68 Glucosylceramide synthase (GCS), 230 Glycerophospholipids, 232 J Glycosphingolipids (GSLs), 230, 237 Jurkat T cells, 235 Glycosyl phosphatidyl inositol (GPI), 239 Juxtamembrane region, 139 Glycosylation, 266, 267, 269 Glycosylphosphatidylinositol (GPI), 28, 30, 40, 46 K Glycosylphosphatidylinositol (GPI) carboxyl Kaposi sarcoma-associated herpes virus terminus, 255 (KSHV), 261 Glycyrrhiza glabra (liquorice), 112 Karray’s group, 144 Golgi apparatus, 230, 231 3-Ketodihydrosphingosine (3-KDS), 230 GPI. See Glycosylphosphatidylinositol (GPI) Kit-ligand, 113 Graft-versus-host disease (GvHD), 111 Krammer’s laboratory, 135 GRP-78, 99–101 Kupffer cell apoptosis, 112 GST-hTNFR2 fusion protein, 62

L H Lewis-Lung Carcinoma (LLC) cells, 102 Haematopoiesis, 110, 114 Licochalcone A, 112 Haematopoietic cells, 120 Linear ubiquitin chain assembly complex HDAC inhibition (HDACi), 119 (LUBAC), 63, 64, 169 Hepatocyte growth factor (HGF), 114 Lin-Sca-l-c-kit+ progenitor cells, 110 Histone deacetylase inhibitors (HDAC), 7, 12 Lipid rafts, Fas/CD95 Human CD95L protein (hCD95L), 138 apoptotic molecules, 208 Human cytomegalovirus (HCMV), 256 CASMER, 197, 198 Human HSCs, 110 ceramide, 199–201 Human Par-4, 93 death receptors and signalling molecules, 197 definition, 188 edelfosine, 196 I FADD and procaspase-8, 197 IAP. See Inhibitor of apoptosis proteins (IAP) PI3K/Akt signalling pathway, 202–203 IAP-binding motif (IBM) protein–protein interactions, 197 characteristic, 60 semaphorin 3A (Sema3A), 203 Smac and HtrA2, 61 S-palmitoylation and post-translational unconventional, 61 modifications, 201, 202 IAP-like protein 2 (ILP2), 60, 61 TRAIL and DISC, 198, 199 Ibrutinib, 113 traumatic brain injury, 197 Index 313

LNCaP cell line, 140 Mouse models LNCaP prostate cancer cells, 96 CD95L affinity, 142 Lyapunov exponents, 300 gld and lpr mice, 142 Lymphoproliferation (Lpr), 133 NF-κB and MAPK cues, 142 Lymphotoxin β receptor (LTβR), 115 Mouse TRAIL (mTRAIL), 119 Lymphotoxin-alpha (LTα), 261 MSC-derived pre-osteoblasts FASL, 112 MSC-TRAIL experimental studies, 117 Murine fibrosarcoma L929 cell line, 240 M Murine Lin-Sca-1+c-kit+ stem cells, 110 Mapatumumab, 5 Myelodysplastic syndrome, 113 Melanoma Myristoylation, 265 angagonize XIAP, 86 antitumor strategy, 85 apoptosis (see Apoptosis) N apoptosis deficiency, 79–80 Na+/H+ exchanger 1 (NHE1), 141 Bax activation, 85 Necroptosis Bcl-2 proteins, 84–85 RIPK1-dependent complex II, 64 caspase-3 and 8, 86 synergistic induction, 67 cytotoxic T-lymphocytes, 80 TNFα-induced, 67 immune modulators, 80 Neuronal apoptosis inhibitory protein (NAIP), mitochondrial pathways, 83–84 59, 61 multiple strategies, 83 NF-κB signalling, 62, 64 permanent and inducible NFκB transcription factor, 99 resistance, 82 NO donor nitrosylcobalamin (NO-Cbl), 265 proapoptotic programs, 80 Nogo-receptor, 256 TRAIL sensitization, 84 Non-apoptosis signalling pathways, 108 Memory T-cells, 145–146 Non-apoptotic functions, 110, 111 Mesenchymal stem cells (MSCs), 5 Non-conventional TNFSF/TNFRS ligands, 255 Akt inhibitor, 119 Non-haematopoietic cell precursors, 114 anti-apoptotic protein, 116 Non-TNFSF ligands, 255 Bax and Bak oligomerisation, 118 Nuclear factor κB (NF-κB) Bcl-2 family, 117 absence of survival factors, 62 BM-derived, 114 cIAP proteins, 66 CCA, 119 MAPK activation, 64 cytotoxic T cell functions, 114 Nuclear Localization Sequences, 94 death receptors, 115–119 Nuclear localization signal (NLS), 7 HDACi, 119 HSCs and ESCs, 119–120 immune-regulatory properties, 115 O ISCT, 114 O- and N-glycosylation, 266–269 mechanisms, 115 Oligomerisation, 108 NF-κB and PKB/Akt, 119 Oncogenic K-Ras mutations, 97 treatments, 119 Oncogenic Ras, 97 XIAP inhibitors, 118 OPG. See Osteoprotegerin (OPG) Metalloproteases, 261, 262 Ordinary differential equations (ODEs), Methyltransferase inhibitors, 103 293, 304 Methyl-β-cyclodextrin, 233 Osteoarthritis, 140 Mitochondrial outer membrane Osteoprotegerin (OPG), 30, 31 permeabilization (MOMP), 295–297, 300, 304, 305 Mitochondrial transport, 296 P Motility-inducing signalling complex (MISC), p38 signalling, 62 137, 138, 237–239 Palmitoyl coenzyme A (palmitoyl-CoA), 230 314 Index

Palmitoylation, 264–265 and TRAIL, 100–101 Pancreatic cancer cells, 118, 119 Protein–protein interactions (PPIs), 136 Par-4 colocalizes, 101 Proteolytic cleavage Par-4 S249 residue, 96 TNFRSF, 262 PAWR, 93 TNFSF, 261–262 pCAGGS vector, 101 Perifosine, 119 Phosphocholine headgroup, 230 R PI3K/AKT signaling, 97 Radiosensitivity, 93 PI3K/AKT/mTOR pathways, 82 Raf-MEK-ERK pathways, 98 PI3K-AKT pathway, 96 RAS/RAF/MEK/ERK pathways, 82 PLAD. See Pre-ligand binding assembly Really Interesting New Gene (RING) domain, domain (PLAD) 60–62 Pluripotent embryonic stem cells, 109 Receptor-induced apoptosis Posttranslational modifications (PTMs) anticancer strategy, 292 DISC interferes, 261 biochemical rates, 304 significance, 263–264 cell lines and sensitivities, 299–301 TNFRSF, 262 computational approaches, 292 TNFSF, 261–262 and cycloheximide, 304 TNFSF/TNFRSF family, 261 death ligand–receptor, 292 Pre-ligand binding assembly domain (PLAD), early efforts, 293 28, 30, 42, 43, 46 in vitro studies, 305 Proapoptotic Bcl-2 proteins, 81, 82 individual cells, 297–299 Pro-apoptotic caspase-9 and Bcl-x(s) inhomogeneities, 305 expression, 236 kinetic modeling and quantitative Pro-apoptotic factors, 108 experimental data, 294–296 Pro-apoptotic mitochondrial factors, 80 MOMP regulators, 305 Pro-apoptotic signalling pathways, 81 nonsurgical cancer therapies, 292 Prostaglandin E2 (PGE2), 114 ODE models, 304 Prostate apoptosis response-4 (Par-4) phenotypic heterogeneity, 292 AKT, K-Ras, and Src—subcellular pro- and anti-apoptotic proteins, 304 ruffians, 96–98 process, 303 anti-Par-4 antibody, 103 protein levels, 301–303 apoptotic liver damage, 92 Receptor-interacting protein homotypic Arylquin-1, 103 interaction motif (RHIM), 163, breast cancer recurrence, 93 168, 169 cancer, 92 Receptor-interacting protein kinase 1 (RIPK1), chemotherapeutic agents, 92 63–65, 67 chemotherapeutic response, 93 adaptor TRADD, 63 and death receptors, 98–101 CD95L-mediated cell death, 67 EGFR, Ras, and Src, 92 cIAPs themselves, 64 endogenous factor, 102 homotypic DD interaction, 64 ER stress, 93 Restimulation induced cell death (RICD), 147 extracellular secretion, 103 Rheumatoid arthritis, 140 and GRP-78, 99–100 RHIM. See Receptor-interacting protein intrinsic activity, 93 homotypic interaction motif (RHIM) leucine zipper, 95–96 nuclear localization sequence domains, 95, 96 Nutlin-3 and PS1145, 102 S renal cell carcinomas, 93 Selective for Apoptosis of Cancer Cells (SAC) SAC domain, 94–95 domain, 94–95, 100, 102 SAC transgenic mice, 101–102 Serial analysis of gene expression (SAGE), 111 structure, 93–94 Sertoli cells, 136 Index 315

Signal Temporal Logic (STL), 300, 301 T Signal transduction T lymphocytes, 133 death-receptors, 257–260 TAAs. See Tumor-Associated Antigens (TAAs) pathways, 297 tBid-induced MOMP, 236 TNFRSF receptor glycosylation, 268 T-cell activation, 146–148 Smac mimetic AEG40730, 66–67 αβ T-cell receptor (TCR), 131 Smac mimetics T-cells, 144–145 CD95, 67 Terminal dUTP nick end labelling TNFα-induced necroptosis, 66, 67 (TUNEL), 120 TRAIL, 68–69 Th1/Th17 immune responses, 112 Smac release, 295 Th17 cells, 132, 146, 147 Smac/XIAP rheostat, 83 Thapsigargin, 99 SMase activation, 241 Thrombopoietin (TPO), 110 S-nitrosylation, 265–266 TLR3. See Toll-like Receptor 3 (TLR3) Soluble TRAIL trimers (sTRAIL), 264 TLR4-ERK1/2-FAS/FASL-caspase-3 axis, 112 Sphingolipids (SLs) T-lymphocytes, 136, 144, 145 aSMase deficiency, 231 TNF family CD95L-induced apoptosis, 232 harbor putative PTM sites, 270 CD95L-induced cell motility, 238 ligands and receptors, 248 CD95-mediated cell apoptosis TNFRSF, 248–256 (see CD95-mediated cell apoptosis) TNFSF, 248 ceramidases, 231 TNF receptor (TNFR), 136 “de novo” biosynthesis pathway, 230 TNF receptor 1-associated death domain DR redistribution, 241 protein (TRADD), 134, 136 Golgi apparatus and ceramide, TNF receptor family, 136–137 230, 231 TNF superfamily member (TNFSF), 28 3-KDS, 230 TNF-α converting enzyme (TACE), 257, 261 sphingosine, 230 TNFR superfamily member (TNFRSF), subcellular compartmentalization, 231 29, 31 TRAIL signalling, 239–241 TNFR1 signalling, 63 Sphingomyelin (SM), 230, 231, 233–235, TNFR2 signalling, 62 237, 240 TNF-related apoptosis-inducing ligand Sphingomyelinase (SMase), 232, 233, 241 (TRAIL), 64–66, 68, 69, 80, 100, Sphingosine 1 phosphate (S1P) signalling 101, 197–199, 204, 207, 208 pathway, 147 TNFRSF. See TNFR superfamily member Src/PI3K/AKT/mTOR pathway, 111 (TNFRSF) Staphylococcal enterotoxin B TNFSF/TNFRSF ligand/receptor (SEB), 145 signalling, 270 Stem cell regulation TNFSF/TNFRSF signalling, 269 apoptosis, 108 Toll-like Receptor 3 (TLR3) death domain, 108 anti-cancer drugs, 170 death receptor–ligand signalling, 108 cancer cells diabetes and heart diseases, 109 apoptosis induction, 168 ESCs, 109 caspase-8, 168 FASL, 111–112 c-Myc-dependent cell proliferation, 170 tBid protein, 108 epithelial, 167 TNF, 109–111 heterogeneity, 167 TNFSF family, 109 mRNA, 162, 166 TRADD and FADD, 108 necroptosis, 169 TRAIL, 113–114 pharyngeal and papillary thyroid SV40-transformed human fibroblasts, 234 cancer, 170 Systemic lupus erythematosus (SLE), 137, proliferation, 167 140, 147, 263 tumor data, 166 316 Index

Toll-like Receptor 3 (TLR3) (cont.) heteromeric complexes, 41–44 chemotherapeutic agents, 170 homo- and heteromeric complexes, 43 dsRNA (see Double-stranded RNAs intracellular signalling, 44 (dsRNAs)) mathematical modelling, 44 5-fluorouracil, 170 regulatory receptor, 43 immunogenic activity, 171 signalling complex, 41–43 sides effects, 166 TRAIL-R4, TRAIL-R4-α and TRAIL- signal transduction pathways, 160 R-β, 31 synthetic ligands, 165–166 TRAIL receptor inducer of cell killing 2 tumor autovaccination, 171–174 (TRICK2), 29 Topoisomerase I (TOPO-I), 95, 96 TRAIL Receptor with a truncated Death TRAIL. See Tumor necrosis factor-related Domain (TRUNDD), 31 apoptosis-inducing ligand (TRAIL) TRAIL Receptor without an Intracellular TRAIL receptor Domain (TRID), 31 apoptosis, 32–33 TRAIL resistance colorectal cancers, 36 acquisition, 10–11 conventional chemotherapy, 36 AMG 655, dulanermin, lexatumumab, and DcR3 gene, 31 apomab, 11 expression pattern chemotherapeutic agents and acute myeloid/acute lymphoblastic radiotherapies, 12 leukaemia, 38 death receptor expression levels, 12 breast cancer, 37 HDAC, 12 colorectal cancer, 37 leukemia and lymphoma, 11 cytoplasmic TRAIL, 37 mapatumumab and sorafenib, 12 genetic loss, 36 mechanisms, 10 glioblastoma multiforme, 37 pancreatic cancer cells, 11 non-small cell lung cancer, 37 small molecule ONC201, 11 nuclear TRAIL-R2, 37 TRAIL+CHX treatments, 297–299 oral and cervical carcinoma, 38 TRAMP- and DR6-induced signal polymorphisms, TRAIL-R1 and transduction, 259 TRAIL-R2, 37 Transforming growth factor-β activated kinase pro-apoptotic proteins, 36 1 (TAK1), 61 TRAIL-R2 upregulation, 38 Transmembrane CD95L, 140 TRAIL-R3 and TRAIL-R4, 38 Triple-negative breast cancer (TNBC), 237, in vivo 238, 263 endothelium, 35 Truncated Bid (tBid), 65, 66, 108 germ cell apoptosis, 35 Tumor necrosis factor superfamily (TNFSF) immune responses, 34 cleavage, 261–262 malignant cells, 35 independent signalling pathways, 256 NK cells, 34 and TNFRSFs, 255, 266 viral and bacterial infections, 35 type II transmembrane glycoproteins, 248 membrane receptors, 30 Tumor necrosis factor-related apoptosis- necroptosis, 33 inducing ligand (TRAIL) non-cytotoxic signalling, 33–34 biomarker development and genetic OPG, 31 sequencing, 14 pro-survival pathways, 45–46 caspase signalling and activation, 9 radiotherapy and chemotherapy, 36 caspase-8 expression, 10 structure, 28–29 Cathepsin E, 2 TRAIL-R1 and TRAIL-R2, 29, 31 cell death, 1 TRAIL-R1 to TRAIL-R4, CRDs, 30 cell-based delivery, 5 TRAIL-R3, 31 cytotoxicity, 6 TRAIL-R3 and TRAIL-R4 death receptor expression, 6–7 apoptotic signalling network, 40 death receptor knockout mouse model, 4 cancer cell lines, 40 decoy receptors, 8 decoy model, 40–41 DISC and FADD, 8–9 Index 317

DR4 and DR5 gene expression, 2 Tumour necrosis factor receptor superfamily DR5 upregulation, 6 (TNFRSF), 108 extrinsic pathway, 2–3 Tumour necrosis factor superfamily FDA-approved therapies, 14 (TNFSF), 109 HDAC, 7 Tunicamycin, 99 hepatocytes and astrocytes, 4 Type II Jurkat leukemia T cells, 234 IAP (see Inhibitor of apoptosis proteins Type III virulence secretion system (T3SS), 266 (IAP)) immune cells, 5 intrinsic pathway, 3 U malignant cells, 4 Unfolded protein response (UFP), 99 Mapatumumab, 5 metastasis, 3–4 nanoliposomes and E-selectin (ES), 5 V normal cells, 10 Vemurafenib, 82 N-terminal PEGylated TRAIL, 5 Very severe aplastic anaemia (vSAA), 113 ONC201, 6, 7 receptor antibodies, 5–6 receptor trimerization and conformational W change, 2 Wilms’ tumor protein (WT-1), 95, 96 therapies and delivery strategies, 13 Tumor-associated antigens (TAAs), 172, 174 Tumour necrosis factor (TNF) X apoptosis, 28 X-linked hypohidrotic ectodermal dysplasia cell death induction, 28 (XLHED), 263 co-stimulatory signalling, 27–28 X-linked inhibitor of apoptosis protein Fas/CD95 (see Fas/CD95) (XIAP), 3, 9, 10, 60, 61, 66, 68 homotrimeric type I transmembrane proteins, 28 ligand bioactivity, 28 (see also TRAIL Z receptor) ZIP-kinase (ZIPK), 95