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Chapter 4 Kinome profiling of non‐canonical TRAIL signaling reveals RIP1‐Src‐STAT3 dependent invasion in resistant non‐small cell lung cancer cells Kaamar Azijli, Saravanan Yuvaraj, Maikel P. Peppelenbosch, Thomas Würdinger, Henk Dekker, Jos Joore, Evert van Dijk, Wim J. Quax, Godefridus J. Peters, Steven de Jong, Frank A.E. Kruyt Journal of Cell Science, 2012; 125, 4651‐4661
Chapter 4 ABSTRACT Tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) triggers apoptosis selectively in tumor cells through interaction with TRAIL‐R1/DR4 or TRAIL‐R2/DR5 and is considered a promising avenue in cancer treatment. TRAIL resistance, however, is frequently encountered and hampers anti‐cancer activity. Here we show that whereas H460 non‐small cell lung cancer (NSCLC) cells display canonical TRAIL‐dependent apoptosis, A549 and SW1573 NSCLC cells are TRAIL resistant and display pro‐tumorigenic activity, in particular invasion, following TRAIL treatment. We exploit this situation to contrast TRAIL effects on the kinome of apoptosis‐sensitive cells to that of NSCLC cells in which non‐canonical effects predominate, employing peptide arrays displaying 1,024 different kinase pseudosubstrates more or less comprehensively covering the human kinome. We observed that failure of a therapeutic response to TRAIL coincides with the activation of a non‐canonical TRAIL‐induced signaling pathway constituting amongst others of the activation of Src, STAT3, FAK, ERK and Akt. The use of TRAIL‐R1 or TRAIL‐R2 selective TRAIL variants subsequently showed that this non‐canonical migration and invasion is mediated via TRAIL‐R2. Short‐hairpin‐mediated silencing of RIP1 kinase prevented TRAIL‐induced Src and STAT3 phosphorylation and reduced TRAIL‐induced migration and invasion of A549 cells. Inhibition of Src or STAT3 by shRNA or chemical inhibitors including dasatinib and 5,15‐DPP blocked TRAIL‐induced invasion. FAK, Akt and ERK were activated in a RIP1‐independent way and inhibition of Akt sensitized A549 cells for TRAIL‐induced apoptosis. We thus identified RIP1‐dependent and ‐independent non‐ canonical TRAIL kinase cascades in which Src and Akt are instrumental and could be exploited as co‐targets in TRAIL therapy for NSCLC. Key Words: TRAIL, migration, NSCLC, RIP1, kinome profiling, Src inhibitors ‐ 60 ‐
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TRAIL-induced kinases activation an
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TRAIL‐induced kinases activation
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“In order to be irreplaceable one
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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 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 41 and 42: Chapter 3 ABSTRACT Tumor necrosis f
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 59: 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 99 and 100: Chapter 5 ‐ 98 ‐
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
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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 7 ‐ 134 ‐
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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 8 ‐ 144 ‐
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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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