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Non‐canonical TRAIL signaling apoptotic activity is neutralized by the release of second mitochondria‐derived activator of caspase (SMAC) from mitochondria [19]. More recently, death receptors have been discovered to trigger another way to die, named necroptosis. This caspase‐independent form of regulated necrotic cell death has been mostly studied in TNF receptor signaling and appears important for the regulation of immunity and inflammation [20]. TNF‐ induced necroptosis depends on the activation of receptor interacting protein 1 (RIP1; also known as RIPK1), and RIP3 (also known as RIPK3), in a complex consisting of TRADD, FADD and caspase‐8. Recently TRAIL was found to activate necroptosis in tumor cells under acidic extracellular pH conditions, involving RIP1 and RIP3 [21]. Whether TRAIL can also induce the formation of a similar, so‐called ‘necroptosome’ complex, consisting of amongst others RIP1/RIP3 remains to be shown. Figure 1. The TRAIL apoptotic pathway. Simplified and schematic representation of the pathway. Binding of TRAIL or generated agonistic agents to the TRAIL receptors results in the recruitment of FADD and procaspase‐8, also known as the DISC. Subsequently, caspase‐8 cleavage in the DISC can activate downstream caspase‐3, leading to the induction of apoptosis (extrinsic pathway). The caspase‐8 analogue cFLIP can compete for FADD binding and inhibit DISC formation. Caspase‐8 can also cleave the Bcl‐2 family member Bid into tBid engaging the intrinsic pathway by binding to Bax causing mitochondrial membrane permeabilization and the release of apoptogenic factors such as cytochrome c. Pro‐survival Bcl2 family members can prevent mitochondrial permeabilization. IAPs, such as XIAP, can bind to caspases and inhibit apoptosis. Necroptosis, a regulated form of caspase‐independent necrotic cell death, can also be activated through TRAIL receptors under specific conditions. This involves the activation of RIP1 and RIP3 in a complex that has not been precisely clarified as yet. See text for more details. ‐ 19 ‐
Chapter 2 In preclinical studies, approximately half of the tumor cells show resistance towards TRAIL‐induced apoptosis, but combined treatment with various standard or experimental agents can re‐sensitize these cells (reviewed in [22;23]. Intrinsic TRAIL resistance in tumor cells involves blockades at different levels in the pathway, such as high levels of decoy receptors, limitations in DISC formation due to cFLIP‐mediated inhibition, posttranslational modifications of DISC proteins, and high expression of anti‐apoptotic Bcl‐ 2 proteins that inhibit mitochondrial apoptosis. Combined therapy with standard chemo‐ and radiotherapy as well as a number of targeted agents can overcome these apoptotic blockades. Commonly these agents act by upregulation of TRAIL receptors and downregulation of anti‐apoptotic proteins resulting in enhanced DISC formation and mitochondria‐dependent apoptosis [24‐32]. The promising antitumor activity in preclinical models has spurred early clinical studies with TRAIL receptor agonists in various tumor types [33‐37]. However, as described below, recent preclinical findings indicate pro‐survival, proliferation and even metastatic activity of TRAIL, suggesting more caution when applying these TRAIL receptor agonists, particularly as single agents. In this review we will give an update on the non‐canonical (non‐apoptotic) signaling activity of the TRAIL pathway in tumor and non‐transformed cells. The different kinase cascades involved are described and the consequences for TRAIL‐based therapy are discussed. TRAIL RECEPTOR SIGNALING COMPLEXES AND KINASE ACTIVATION The early molecular events leading to non‐canonical TRAIL signaling are complex and not well understood. Co‐immunoprecipitation experiments have indicated the formation of a so‐called secondary signaling complex subsequent to the assembly of the primary DISC [38]. This secondary complex was found to contain RIP1, TNF receptor associated factor 2 (TRAF2) and NF‐ĸB essential modulator (NEMO)/IKKγ in addition to FADD and active caspase‐8. In this context, the localization of the TRAIL receptors in the cell membrane also appears to play a role in complex formation. In particular TRAIL receptor localization in lipid rafts enables apoptosis activation [39]. Lipid rafts are plasma membrane domains enriched in cholesterol and glycolsphingolipids function as signaling platforms that serve colocalization of requisite components. In the same study, TRAIL receptors complex assembly outside the rafts was associated with non‐canonical signaling, mediated by RIP and cFLIP [39]. Aggregation of the TRAIL‐R1 and ‐R2 in lipid rafts also occurred only in TRAIL sensitive non‐small lung cancer (NSCLC) H460 cells and not in the resistant A549 cells [40]. Whether lipid raft localization of TRAIL receptors is a consequence or a cause of DISC formation remains to be proven. Additional layers of regulation are provided by the expression of DISC inhibitors, such as cFLIP, and the phosphorylation and/or ubiquitination of several TRAIL receptor‐interacting proteins, including caspase‐8 and RIP1, which has been more extensively reviewed ‐ 20 ‐
Page 2 and 3: TRAIL-induced kinases activation an
Page 4 and 5: TRAIL‐induced kinases activation
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Page 11 and 12: Chapter 1 GENERAL INTRODUCTION Canc
Page 13 and 14: Chapter 1 OUTLINE OF THE THESIS As
Page 15 and 16: Chapter 1 Reference List 1. Jemal A
Page 17 and 18: Chapter 2 ABSTRACT Tumor necrosis f
Page 19: Chapter 2 INTRODUCTION The death li
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Page 31 and 32: Chapter 2 adhesion molecules [109].
Page 33 and 34: Chapter 2 Reference List 1. Ashkena
Page 35 and 36: Chapter 2 37. Tolcher AW, Mita M, M
Page 37 and 38: Chapter 2 melanoma cells from TRAIL
Page 39 and 40: Chapter 2 and ERK pathways. Circula
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Page 49 and 50: Chapter 3 Figure 2 (continued). (e)
Page 51 and 52: Chapter 3 previously established H4
Page 53 and 54: Chapter 3 effect on TRAIL‐induced
Page 55 and 56: Chapter 3 induced apoptosis in H460
Page 57 and 58: Chapter 3 Reference List 1. Jemal A
Page 59 and 60: Chapter 3 40. Domina AM, Vrana JA,
Page 63 and 64: Chapter 4 role in the activation of
Page 65 and 66: Chapter 4 the tip with a diameter o
Page 67 and 68: Chapter 4 RESULTS TRAIL induces a s
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Chapter 4 Non‐canonical TRAIL res
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Chapter 4 A549‐shRIP1 cells clear
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Chapter 4 Figure 7. Inhibition of S
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Chapter 4 DISCUSSION The TRAIL rece
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Chapter 4 Src‐independent mechani
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Chapter 4 variants. Cell Death Dis
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Chapter 4 ‐ 82 ‐
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Chapter 5 ABSTRACT TRAIL is an inte
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Chapter 5 targets and subsequent pr
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Chapter 5 RESULTS Synergistic activ
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Chapter 5 ng/ml TRAIL (Fig. 3B). Ap
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Chapter 5 by sub‐G1 levels in the
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Chapter 5 DISCUSSION In the present
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Chapter 5 Reference List 1. Jemal A
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Chapter 6 ABSTRACT TRAIL is a tumor
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Chapter 6 various stress stimuli [1
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Chapter 6 Subsequently, the membran
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Chapter 6 B H460 A549 Figure 1. Rep
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Chapter 6 TRAIL‐dependent cell de
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Chapter 6 B H460 A549 C Figure 4 (c
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Chapter 6 Figure 5 (continued). Mec
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Chapter 6 regulation and checkpoint
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Chapter 6 mechanism of immune evasi
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Chapter 7 ABSTRACT Thymidine phosph
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Chapter 7 Figure 1. Schematic overv
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Chapter 7 that was measured before
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Chapter 7 RESULTS TdR conversion to
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Chapter 7 dR is secreted from the c
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Chapter 7 Figure 4. Accumulation of
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Chapter 7 angiogenic properties. Ho
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Chapter 7 activity of enzymes. Natu
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Chapter 8 SUMMARIZING DISCUSSION AN
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Chapter 8 Recently, various differe
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Chapter 8 in phase II clinical tria
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Chapter 8 Reference List 1. Herbst
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Chapter 9 NEDERLANDSE SAMENVATTING
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Chapter 9 waargenomen. Het gebruik
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Chapter 9 CONCLUSIE Het activeren v
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zelfs na werktijden (lees 23:45) ko
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Verder wil ik ook dr. Eric Ronken b
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