towards improved death receptor targeted therapy for ... - TI Pharma

More documents

Recommendations

Info

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
Page 6: “In order to be irreplaceable one
Page 9 and 10: ‐ 8 ‐
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
Page 23 and 24: Chapter 2 Table 1| Summary of the k
Page 25 and 26: Chapter 2 proliferation could be pr
Page 27 and 28: Chapter 2 Figure 2. Canonical and n
Page 29 and 30: Chapter 2 associated with TRAIL res
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
Page 43 and 44: Chapter 3 inhibitors and TRAIL rece
Page 45 and 46: Chapter 3 of amplification of the t
Page 47 and 48: Chapter 3 P38 and JNK have opposing
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
Page 69 and 70: Chapter 4 vehicle control or with 5
Page 71 and 72:
Chapter 4 Non‐canonical TRAIL res
Page 73 and 74:
Chapter 4 A549‐shRIP1 cells clear
Page 75 and 76:
Chapter 4 Figure 7. Inhibition of S
Page 77 and 78:
Chapter 4 DISCUSSION The TRAIL rece
Page 79 and 80:
Chapter 4 Src‐independent mechani
Page 81 and 82:
Chapter 4 variants. Cell Death Dis
Page 83 and 84:
Chapter 4 ‐ 82 ‐
Page 85 and 86:
Chapter 5 ABSTRACT TRAIL is an inte
Page 87 and 88:
Chapter 5 targets and subsequent pr
Page 89 and 90:
Chapter 5 RESULTS Synergistic activ
Page 91 and 92:
Chapter 5 ng/ml TRAIL (Fig. 3B). Ap
Page 93 and 94:
Chapter 5 by sub‐G1 levels in the
Page 95 and 96:
Chapter 5 DISCUSSION In the present
Page 97 and 98:
Chapter 5 Reference List 1. Jemal A
Page 99 and 100:
Page 101 and 102:
Chapter 6 ABSTRACT TRAIL is a tumor
Page 103 and 104:
Chapter 6 various stress stimuli [1
Page 105 and 106:
Chapter 6 Subsequently, the membran
Page 107 and 108:
Chapter 6 B H460 A549 Figure 1. Rep
Page 109 and 110:
Chapter 6 TRAIL‐dependent cell de
Page 111 and 112:
Chapter 6 B H460 A549 C Figure 4 (c
Page 113 and 114:
Chapter 6 Figure 5 (continued). Mec
Page 115 and 116:
Chapter 6 regulation and checkpoint
Page 117 and 118:
Chapter 6 mechanism of immune evasi
Page 119 and 120:
Chapter 7 ABSTRACT Thymidine phosph
Page 121 and 122:
Chapter 7 Figure 1. Schematic overv
Page 123 and 124:
Chapter 7 that was measured before
Page 125 and 126:
Chapter 7 RESULTS TdR conversion to
Page 127 and 128:
Chapter 7 dR is secreted from the c
Page 129 and 130:
Chapter 7 Figure 4. Accumulation of
Page 131 and 132:
Chapter 7 angiogenic properties. Ho
Page 133 and 134:
Chapter 7 activity of enzymes. Natu
Page 135 and 136:
Page 137 and 138:
Chapter 8 SUMMARIZING DISCUSSION AN
Page 139 and 140:
Chapter 8 Recently, various differe
Page 141 and 142:
Chapter 8 in phase II clinical tria
Page 143 and 144:
Chapter 8 Reference List 1. Herbst
Page 145 and 146:
Page 147 and 148:
Chapter 9 NEDERLANDSE SAMENVATTING
Page 149 and 150:
Chapter 9 waargenomen. Het gebruik
Page 151 and 152:
Chapter 9 CONCLUSIE Het activeren v
Page 153 and 154:
zelfs na werktijden (lees 23:45) ko
Page 155 and 156:
Verder wil ik ook dr. Eric Ronken b
show all

towards improved death receptor targeted therapy for ... - TI Pharma

Create successful ePaper yourself

Delete template?

Save as template?