Background: TRAIL is a potent and specific inducer of apoptosis in tumour cells and therefore is a possible new\ncancer treatment. It triggers apoptosis by binding to its cognate, death-inducing receptors, TRAIL-R1 and TRAIL-R2.\nIn order to increase its activity, receptor-specific ligands and agonistic antibodies have been developed and some\ncancer types, including pancreatic cancer, have been reported to respond preferentially to TRAIL-R1 triggering. The\naim of the present study was to examine an array of TRAIL-receptor specific variants on a number of pancreatic\ncancer cells and test the generality of the concept of TRAIL-R1 preference in these cells.\nMethods: TRAIL-R1 and TRAIL-R2 specific sTRAIL variants were designed and tested on a number of pancreatic\ncancer cells for their TRAIL-receptor preference. These sTRAIL variants were produced in HEK293 cells and were\nsecreted into the medium. After having measured and normalised the different sTRAIL variant concentrations, they\nwere applied to pancreatic and control cancer cells. Twenty-four hours later apoptosis was measured by DNA\nhypodiploidy assays. Furthermore, the specificities of the sTRAIL variants were validated in HCT116 cells that were\nsilenced either for TRAIL-R1 or TRAIL-R2.\nResults: Our results show that some pancreatic cancer cells use TRAIL-R1 to induce cell death, whereas other\npancreatic carcinoma cells such as AsPC-1 and BxPC-3 cells trigger apoptosis via TRAIL-R2. This observation extended\nto cells that were naturally TRAIL-resistant and had to be sensitised by silencing of XIAP (Panc1 cells). The measurement\nof TRAIL-receptor expression by FACS revealed no correlation between receptor preferences and the relative levels of\nTRAIL-R1 and TRAIL-R2 on the cellular surface.\nConclusions: These results demonstrate that TRAIL-receptor preferences in pancreatic cancer cells are variable and that\npredictions according to cancer type are difficult and that determining factors to inform the optimal TRAIL-based\ntreatments still have to be identified.
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