title: Non-canonical kinase signaling by the death ligand TRAIL in cancer cells: discord in the death receptor family.
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, IκB/ 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 who will likely benefit from TRAIL-based therapy and could provide a rationalized basis for combination therapies with TRAIL death receptor-targeting drugs.
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Azijli
authors.forename: B
authors.initials: B
authors.lastname: Weyhenmeyer
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
authors.forename: S
authors.initials: S
authors.lastname: de Jong
authors.forename: F A E
authors.initials: FA
authors.lastname: Kruyt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D010770:Phosphotransferases / Q000502:physiology*; D053218:Receptors, Death Domain / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D010770:Phosphotransferases; D051550:I-kappa B Kinase; D020929:Mitogen-Activated Protein Kinase Kinases