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

More documents

Recommendations

Info

Non‐canonical TRAIL signaling elsewhere [16;41;42]. Regardless of the more precise composition and regulation of the complexes involved, non‐canonical TRAIL receptor‐induced kinase activation has been reported in various cell‐ and tumor types. These cascades were demonstrated to result in proinflammatory, proliferative, survival and migratory responses and are in more detail discussed below. IĸB/ NF‐κB SURVIVAL SIGNALING Activation of the inflammatory and cell survival pathway controlled by the transcription factor NF‐ĸB was one of the first reported non‐canonical signals elicited by TRAIL (see Figure 2 and Table 1). Both TRAIL‐R1 and –R2 were found to activate NF‐ĸB in a TRADD and RIP1‐dependent way [43‐45]. NEMO (IKK‐γ) was found to be part of the secondary complex, able to recruit IKKα/β to the signaling complex causing the phosphorylation and subsequent proteasomal degradation of the inhibitor of kβ (IĸB), leading to release and accumulation of NF‐ĸB [38]. NF‐ĸB then translocates to the nucleus where it can activate the transcription of amongst others the anti‐apoptotic genes cFLIP, Bcl‐xL , Mcl‐1 and cIAPs [46]. In preclinical tumor models such as (primary) leukemia [47], neuroblastoma [48], pancreatic cancer [49], mantle cell lymphoma cells [50] and NSCLC [51], inhibition by overexpression of an IĸB dominant‐negative version or by selective chemical inhibitors enhanced TRAIL apoptosis. Interestingly, NF‐ĸB can have dual activity as it was found to mediate the upregulation of TRAIL receptors on one hand, and enhance Bcl‐xL expression and apoptosis resistance on the other [52]. More recently, a pro‐apoptotic role for NF‐ĸB was demonstrated in glioma cell lines where inhibition of the NF‐ĸB pathway reduced TRAIL‐induced apoptosis via an as yet elusive mechanism [53]. ‐ 21 ‐
Chapter 2 Table 1| Summary of the kinases activated by TRAIL in different tumor types. The functional conesquences of activation being either pro-apoptotic, pro-survival, proliferative or migratory are indicated. Kinase Tumor type Response Reference IĸB/ NF-ĸB leukemia, neuroblastoma, pancreatic, mantle cell lymphoma, NSCLC pro-survival [47-51] glioma pro-apoptotic [52] JNK lymphoid, cholangiocarcinoma pro-apoptotic [56;60;124] hepatocellular carcinoma pro-survival [63] short JNK1 colon pro-survival [65] long JNK1 colon pro-apoptotic [65] p38 ovarian pro-apoptotic [66] prostate, breast pro-survival [68;69] ERK colon, SCLC, melanoma, glioma proliferative [71-74] TAK1 prostate, ovarian pro-survival [68;77] PKC pancreatic pro-survival [79] δ,ε,η melanoma, breast pro-survival [80;81] α,β,γ NSCLC pro-apoptotic [24] PI3K/Akt leukaemia, ovarian, breast, NSCLC, prostate pro-survival [85;89-91] Src prostate, NSCLC, hepatic, breast Migratory/invasive and pro-survival [88;90;94;95] MITOGEN‐ACTIVATED PROTEIN KINASES (MAPKs) IN TRAIL‐SIGNALING MAPKs are enzymes that control important physiological processes, such as gene expression, motility, metabolism, mitosis, and programmed cell death. In mammals six distinct groups of MAPKs have been characterized, extracellular regulated kinases (ERK1/2), Jun NH2 terminal kinases (JNK1/2/3), p38 (p38 α/β/γ/δ), ERK7/8, ERK3/4 and ERK5 [54]. TRAIL can activate JNK, p38 and ERK1/2 in several cancer cell lines with dual effects but mostly contributing to cell proliferation and pro‐survival signalling, as outlined further below. c‐Jun N‐terminal kinases (JNKs) The JNKs are stress‐activated members of the MAP kinase family that can be activated by TRAIL via both caspase‐dependent and ‐independent mechanisms in a cell type‐specific way [55]. FADD appeared to be dispensable for JNK activation. In lymphoid cells, JNK pathway activation by TRAIL contributed to apoptosis activation [56]. JNK activation involved a TRAF2‐MEKK1‐MKK4‐dependent signaling pathway in human embryonic kidney 293 cells [57] and required RIP1 in prostate cancer cells [58]. Both TRAF2 and RIP1 were detected in the secondary complex and were required for JNK activation in fibrosarcoma cells [38]. JNK activation results in phosphorylation of its well‐known target the transcription factor c‐Jun/ AP1, but can also directly phosphorylate the pro‐apoptotic Bcl‐ 2 family member Bim in hepatocytes, thereby stabilizing the protein and facilitating mitochondrial apoptosis [59]. A role for JNK and Bim has also been found in the activation ‐ 22 ‐
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 and 20: Chapter 2 INTRODUCTION The death li
Page 21: Chapter 2 In preclinical studies, a
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?