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Non‐canonical TRAIL signaling of a lysosmal death pathway induced by TRAIL in cholangiocarcinoma cells [60]. Another cell death route was also connected to TRAIL receptor‐dependent activation of JNK; JNK appeared to phosphorylate a key autophagy regulator, Beclin‐1, leading to autophagic cell death in HCT116 cells [61]. Synergistic apoptosis activation by chemotherapy and TRAIL receptor agonists was shown to involve MKK4‐dependent JNK activation. MAPK p38 was also activated and suppression of activation of these kinases by the antioxidant N‐acetyl cysteine prevented synergistic effects [62]. However, in contrast, direct inhibition of JNK by RNA interference or chemical inhibition augmented TRAIL‐induced apoptosis in hepatocellular carcinoma cells [63]. This indicates that JNK can have opposite effects in TRAIL signaling that may be dependent on the cellular context. These dual functions can in part be due to the duration or magnitude of the activation of the pathway. For example, it was found that prolonged activation of JNK by TNF induces apoptosis, whereas transient activation of JNK promotes cell survival [64]. Furthermore, a recent study has shown that in colon cancer cell lines the short JNK1 isoforms (JNK1α1 and JNK1β1) transmit an anti‐ apoptotic signal, whereas the long isoforms (JNK1α2 and JNK1β2) are pro‐apoptotic upon activation of TRAIL [65]. This may also provide an explanation for the dual role of JNK. P38 MAPK Several reports have shown that TRAIL can activate p38 MAPK. P38 activation can occur through the formation of the secondary complex consisting of FADD, caspase‐8, RIP1 and TRAF2 [38]. Lee and co‐workers found TRAIL‐induced p38 activation in Hela cells to be responsible for caspase activation and apoptosis. Elevation of reactive oxygen species (ROS) by TRAIL appeared instrumental for p38 activation [66]. P38 activation by TRAIL was also observed in DLD1 colon cancer cells however; in these cells inhibition of p38 did not affect TRAIL‐mediated cell death [67]. In yet other tumor cells p38 was found to suppress apoptosis. In prostate cancer cells, TRAIL induced p38 phosphorylation causing the transcriptional upregulation of anti‐apoptotic Bcl‐2 family member Mcl‐1, thus rescuing the prostate cancer cells from apoptosis. Inhibition of p38 with chemical inhibitor, SB203580, increased the level of cell death by TRAIL in these cells [68]. Breast carcinoma cells could also be sensitized for TRAIL after inhibition of p38 indicating that this kinase contributes to cell survival in these cells [69]. Thus, p38 can either suppress or enhance the apoptotic effect of TRAIL in a cell type specific way. Extracellular‐signal‐regulated kinases (ERKs) The activation of ERKs by TRAIL has also been reported in a number of reports. In neuroblastoma cells, TRAIL‐induced ERK1/2 phosphorylation [70], and the inhibition of ERK1/2 could enhance TRAIL‐dependent death in colon cancer cells [71]. Even more, in small cell lung cancer (SCLC) cells lacking caspase‐8, TRAIL caused cell proliferation, which was TRAIL‐R2 mediated in some but not all SCLC cell lines tested [72]. TRAIL‐induced ‐ 23 ‐
Chapter 2 proliferation could be prevented by chemical inhibition or siRNA‐mediated knockdown of ERK1/2 identifying this pathway as a critical proliferation mediator [72]. Also in a panel of human melanoma cell lines with variable sensitivities for TRAIL, ERK1/2 phosphorylation were detected within 30 minutes of TRAIL treatment [73]. ERK1/2 inhibition resulted in downregulation of Bcl‐2, Bcl‐xL and Mcl‐1 expression providing an explanation for enhanced TRAIL‐induced mitochondrial apoptosis in these cells. TRAIL resistant human glioma cells also demonstrated enhanced cell proliferation upon TRAIL treatment that could be linked to ERK1/2 activation [74]. ERK inhibition suppressed stimulation of proliferation but did not sensitize for TRAIL. Knockdown of cFLIP on the other hand prevented ERK activation and resulted in partial sensitization for TRAIL‐dependent apoptosis [74]. Thus, the activation of ERK by TRAIL generally has been implicated in stimulation of cell survival and proliferation of tumor cells. As mentioned, the secondary complex and active caspase‐8 have been implicated in MAPK activation [38]. However, an alternative caspase‐8 requiring mechanism was reported by Song and Lee in DU‐145 prostate cancer cells [75]. They found that mammalian sterile 20‐like kinase 1 (Mst1), a ubiquitously expressed serine/threonine kinase and caspase substrate, could activate p38 and JNK through a caspase‐7 cleavage generated 40 kDa form of Mst1. A caspase‐3 generated 36 kDa form of Mst1 could activate ERK [75]. The same group reported MAP3K (MEKK1) and stress‐activated protein/ERK kinase 1 (SEK1) to mediate TRAIL‐induced JNK/p38 phosphorylation also requiring active caspase‐8 [76]. TGF‐β‐activated kinase 1 (TAK1) TAK1 is a member of the MAP3K family and is activated by various cytokines, such as the TGF‐β, TNF‐α, interleukin‐1 (IL‐1), and ligands of the Toll‐like receptors. It is a key regulator of the NF‐κB subunit p65/RelA and MAPKs activity. TRAIL activated TAK1 in Hela cells resulting in p65, JNK and p38 activation; siRNA knockdown or chemical inhibition of TAK1 enhanced TRAIL‐induced apoptosis [77]. The earlier mentioned activation of p38 by TRAIL in prostate cancer cells was preceded and dependent on activation of TAK1 leading to transcriptional upregulation of Mcl‐1 and suppression of apoptosis [68]. Inhibition of TAK1 is an effective approach to increase TRAIL sensitivity as was reported by Morioka and co‐workers, although in their study direct phosphorylation of TAK1 after TRAIL was not demonstrated [78]. In fibroblasts and keratinocytes derived from TAK‐/‐ knockout mice, as well as in tumor cell lines Saos2 and HeLa cells with silenced TAK1 expression, sensitization to TRAIL‐killing was observed independent of NF‐ κB activity. In the absence of TAK1 TRAIL exposure resulted in ROS accumulation and subsequent degradation of cIAP leading to caspase‐3 activation and apoptosis. Overall, TAK1 activation by TRAIL appears to be associated with apoptosis resistance through either affecting NF‐ĸB signaling and/ or JNK, p38 activation. ‐ 24 ‐
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 and 22: Chapter 2 In preclinical studies, a
Page 23: Chapter 2 Table 1| Summary of the k
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
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Page 137 and 138:
Chapter 8 SUMMARIZING DISCUSSION AN
Page 139 and 140:
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
Page 145 and 146:
Page 147 and 148:
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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