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DUAL EFFECTS ON APOPTOSIS BY PROTEIN KINASE C (PKC) Non‐canonical TRAIL signaling A number of studies have reported on the TRAIL receptor‐dependent activation of protein kinase C (PKC) and its isoforms. Activation of PKC by TRAIL in resistant pancreatic adenocarcinoma cells had anti‐apoptotic effects, and PKC inhibition with Gö6983 sensitized for apoptosis [79]. Furthermore, TRAIL‐sensitive cells could be made resistant following PKC activation with phorbol 12‐myristate 13‐acetate (PMA). In apoptosis sensitive melanoma cells, TRAIL stimulated the phosphorylation of PKCδ and PKCε resulting in apoptosis protecting effects [80]. In the same study, activation of PKC by PMA suppressed apoptosis by preventing the translocation and activation of pro‐apoptotic Bax to the mitochondria and subsequent apoptosis. Other studies also reported extracellular stimuli‐dependent activation of PKC, in particular of the isotypes PKCε and PKCη. For example, in breast cancer cells, PKCε caused TRAIL resistance by activating Akt, followed by Hdm2 phosphorylation. Hdm2, on its turn reduced p53 expression, leading to downregulation of Bid and suppression of activation of the mitochondrial pathway [81]. Activation of PKC also inhibited the recruitment of FADD and caspase‐8 resulting in disruption of DISC formation and a decrease in apoptosis [82]. In contrast to the mentioned anti‐apoptotic effects of TRAIL‐ and extracellular‐induced PKC activation, the activation of conventional PKC isoforms (α, β, γ) by PMA or bryostatin‐ 1 was reported to increase the expression of pro‐apoptotic Bad and the TRAIL receptors leading to sensitization for apoptosis by TRAIL [83]. In NSCLC, PKCα and PKCβ increased TRAIL‐R2 expression and sensitized for TRAIL‐induced apoptosis [24]. Thus, it appears that activation of PKCδ, PKCε and PKCη leads to apoptosis inhibition, whereas activation of PKC isoforms α, β and γ enhances apoptosis induced by TRAIL which is cell type dependent. ‐ 25 ‐
Chapter 2 Figure 2. Canonical and non‐canonical TRAIL signalling in cancer cells. Schematic overview of apoptotic, and proliferation/ pro‐survival signals elicited by the activation of TRAIL receptors. Following binding of TRAIL receptor agonists to their death receptors, the DISC can be formed, resulting in apoptosis. A secondary complex can also be formed after TRAIL receptor activation leading to the activation of various kinases and the induction of direct or indirect non‐apoptotic responses as indicated. The more precise molecular events required for secondary complex formation are subject of investigations. The complex could be associated with TRAIL receptors at the membrane or formed in the cytoplasm. See text for more details. PHOSPHATIDYLINOSITIDE 3‐KINASES (PI3K)/AKT SIGNALING COUNTERACTS APOPTOSIS Akt or protein kinase B (PKB) is one of the most critical kinases in the regulation of cell survival. Enhanced activity of the PI3K/Akt pathway is found in many malignancies and is associated with the stimulation of cell growth and cell survival [84]. In leukemic T Jurkat cells, TRAIL phosphorylated PI3K and Akt within 30 minutes, and inhibition of PI3K with the pharmacological inhibitor LY294002 sensitized cells for TRAIL‐induced apoptosis [85]. Sensitization was associated with reduced nuclear translocation of NF‐ĸB p65, reflecting an earlier found direct ability of PI3K/Akt to phosphorylate and transactivate p65 and NF‐ κB signaling upon TNF treatment [86;87]. However, NF‐κB inhibition did not sensitize for ‐ 26 ‐
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 and 20: Chapter 2 INTRODUCTION The death li
Page 21 and 22: Chapter 2 In preclinical studies, a
Page 23 and 24: Chapter 2 Table 1| Summary of the k
Page 25: Chapter 2 proliferation could be pr
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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
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
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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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