title: DAPK2 is a novel modulator of TRAIL-induced apoptosis.
abstract: Targeting molecules involved in TRAIL-mediated signalling has been hailed by many as a potential magic bullet to kill cancer cells efficiently, with little side effects on normal cells. Indeed, initial clinical trials showed that antibodies against TRAIL receptors, death receptor (DR)4 and DR5, are well tolerated by cancer patients. Despite efficacy issues in the clinical setting, novel approaches to trigger TRAIL-mediated apoptosis are being developed and its clinical potential is being reappraised. Unfortunately, as observed with other cancer therapies, many patients develop resistance to TRAIL-induced apoptosis and there is thus impetuous for identifying additional resistance mechanisms that may be targetable and usable in combination therapies. Here, we show that the death-associated protein kinase 2 (DAPK2) is a modulator of TRAIL signalling. Genetic ablation of DAPK2 using RNA interference causes phosphorylation of NF-κB and its transcriptional activity in several cancer cell lines. This then leads to the induction of a variety of NF-κB target genes, which include proapoptotic DR4 and DR5. DR4 and DR5 protein expression is correspondingly increased on the cell surface and this leads to the sensitisation of resistant cells to TRAIL-induced killing, in a p53-independent manner. As DAPK2 is a kinase, it is imminently druggable, and our data thus offer a novel avenue to overcome TRAIL resistance in the clinic.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Hammersmith Hospital Campus, ICTEM, Du Cane Road, London W12 0NN, UK.
authors.forename: C R
authors.initials: CR
authors.lastname: Schlegel
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Hammersmith Hospital Campus, ICTEM, Du Cane Road, London W12 0NN, UK.
authors.forename: A-V
authors.initials: AV
authors.lastname: Fonseca
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Hammersmith Hospital Campus, ICTEM, Du Cane Road, London W12 0NN, UK.
authors.forename: S
authors.initials: S
authors.lastname: Stöcker
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Hammersmith Hospital Campus, ICTEM, Du Cane Road, London W12 0NN, UK.
authors.forename: M L
authors.initials: ML
authors.lastname: Georgiou
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Hammersmith Hospital Campus, ICTEM, Du Cane Road, London W12 0NN, UK.
authors.forename: M B
authors.initials: MB
authors.lastname: Misterek
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Hammersmith Hospital Campus, ICTEM, Du Cane Road, London W12 0NN, UK.
authors.forename: C E
authors.initials: CE
authors.lastname: Munro
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Hammersmith Hospital Campus, ICTEM, Du Cane Road, London W12 0NN, UK.
authors.forename: C R
authors.initials: CR
authors.lastname: Carmo
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Hammersmith Hospital Campus, ICTEM, Du Cane Road, London W12 0NN, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Seckl
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Hammersmith Hospital, Hammersmith Hospital Campus, ICTEM, Du Cane Road, London W12 0NN, UK.
authors.forename: A P
authors.initials: AP
authors.lastname: Costa-Pereira
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D064550:Death-Associated Protein Kinases