towards improved death receptor targeted therapy for ... - TI Pharma
towards improved death receptor targeted therapy for ... - TI Pharma towards improved death receptor targeted therapy for ... - TI Pharma
Chapter 2 Non‐canonical kinase signaling by the death ligand TRAIL in cancer cells: discord in the death receptor family Kaamar Azijli, Birgit Weyhenmeyer, Godefridus J. Peters, Steven de Jong, Frank A.E. Kruyt Cell Death & Differentiation (Accepted, pending revisions)
Chapter 2 ABSTRACT Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐based therapy is currently evaluated in clinical studies as a tumor cell selective pro‐apoptotic approach. However, besides activating canonical caspase‐dependent apoptosis by binding to TRAIL‐specific death receptors, the TRAIL ligand can activate non‐canonical cell survival or proliferation pathways in resistant tumor cells through the same death receptors, which is counterproductive for therapy. Even more, recent studies indicate metastases promoting activity of TRAIL. In this review, the remarkable dichotomy in TRAIL signaling is highlighted. An overview of the currently known mechanisms involved in non‐canonical TRAIL signaling and the subsequent activation of various kinases is provided. These kinases include RIP1, IĸB/ NF‐κB, MAPK p38, JNK, ERK1/2, MAP3K TAK1, PKC, PI3K/Akt and Src. The functional consequences of their activation, often being stimulation of tumor cell survival and in some cases enhancement of their invasive behavior are discussed. Interestingly, the non‐canonical responses triggered by TRAIL in resistant tumor cells resemble that of TRAIL‐induced signals in non‐transformed cells. Better knowledge of the mechanism underlying the dichotomy in TRAIL receptor signaling may provide markers for selecting patients that will likely benefit from TRAIL‐based therapy and could provide a rationalized basis for combination therapies with TRAIL death receptor targeting drugs. Key Words: TRAIL, non‐apoptotic, kinases, metastasis, RIP1 Abbreviations: ADAM, a disintegrin and metalloproteinase; c‐Cbl, Casitas B‐lineage lymphoma; cFLIP, cellular flice‐ like inhibitory protein; DISC, death‐inducing signalling complex; ECs, endothelial cells; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular regulated kinases; FADD, Fas‐ associated protein with death domain; HER, human epidermal receptor; IGF1R, insulin‐like growth factor type 1 receptor; JNK, Jun NH2 terminal kinases; MAPK, Mitogen‐activated protein kinases; Mst1, mammalian sterile 20‐like kinase 1; mTOR, mammalian target of rapamycin; NEMO, NF‐ĸB essential modulator; NF‐κB, Nuclear factor kappa‐light‐chain‐enhancer of activated B cells; NSCLC, non‐small cell lung cancer; OPG, osteoprotegerin; PI3K, Phosphatidylinositide 3‐kinases; PIP3, phosphatidylinositol (3,4,5)‐triphosphate; PKC, protein kinase C; PMA, phorbol 12‐myristate 13‐ acetate; PTEN, phosphatase and tensin homolog deleted on chromosome ten; RIP1, receptor interacting protein kinase 1; RIP3, receptor interacting protein kinase 3; ROCK, Rho kinase; ROS, reactive oxygen species; SEK1, stress‐activated protein/ERK kinase 1; SFK, Src family kinases; SMAC, second mitochondria‐derived activator of caspase; Src, Rous sarcoma oncogene cellular homolog; TAK1, transforming growth factor‐β (TGF‐β)‐activated kinase 1; TGF‐β, transforming growth factor‐β; TRADD, TNF‐receptor‐associated death domain protein; TRAF2, TNF receptor associated factor 2; TRAIL, Tumor necrosis factor‐related apoptosis‐inducing ligand; uPA, urokinase‐type plasminogen activator; VSMCs, vascular smooth muscle cells; XIAP, X‐linked inhibitor of apoptosis protein. ‐ 16 ‐
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Chapter 2<br />
Non‐canonical kinase signaling by the <strong>death</strong> ligand<br />
TRAIL in cancer cells: discord in the <strong>death</strong> <strong>receptor</strong><br />
family<br />
Kaamar Azijli, Birgit Weyhenmeyer, Godefridus J. Peters, Steven de Jong,<br />
Frank A.E. Kruyt<br />
Cell Death & Differentiation (Accepted, pending revisions)
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