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dc.contributor.authorSamali, Afshin
dc.date.accessioned2015-04-17T09:43:17Z
dc.date.available2015-04-17T09:43:17Z
dc.date.issued2013
dc.identifier.citationvan Dijk, M,Halpin-McCormick, A,Sessler, T,Samali, A,Szegezdi, E (2013) 'Resistance to TRAIL in non-transformed cells is due to multiple redundant pathways'. Cell Death & Disease, 4 .en_US
dc.identifier.urihttp://hdl.handle.net/10379/4923
dc.description.abstractTumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine and a selective inducer of apoptosis in a range of tumour cells, but not in normal, untransformed cells. A large number of chemotherapeutics as well as biological agents are being tested for their potential to sensitise resistant tumour cells to TRAIL as a means to broaden the range of tumours treatable with TRAIL. However, because of the incomplete understanding of the mechanism(s) underlying TRAIL resistance in non-malignant cells, it is unpredictable whether the effect of these sensitisers will be restricted to tumour cells or they would also sensitise non-transformed cells causing unwanted toxicity. In this study, we carried out a systematic analysis of the mechanisms driving TRAIL resistance in non-transformed cells. We found that cellular FLICE-like inhibitory protein, anti-apoptotic B-cell lymphoma 2 proteins, and X-linked inhibitor of apoptosis protein were independently able to provide resistance to TRAIL. Deficiency of only one of these proteins was not sufficient to elicit TRAIL sensitivity, demonstrating that in non-transformed cells multiple pathways control TRAIL resistance and they act in a redundant manner. This is contrary to the resistance mechanisms found in tumour cell types, many of them tend to rely on a single mechanism of resistance. Supporting this notion we found that 76% of TRAIL-resistant cell lines (13 out of 17) expressed only one of the above-identified anti-apoptotic proteins at a high level (Z1.2-fold higher than the mean expression across all cell lines). Furthermore, inhibition or knockdown of the single overexpressed protein in these tumour cells was sufficient to trigger TRAIL sensitivity. Therefore, the redundancy in resistance pathways in non-transformed cells may offer a safe therapeutic window for TRAIL-based combination therapies where selective sensitisation of the tumour to TRAIL can be achieved by targeting the single non-redundant resistance pathway.en_US
dc.language.isoenen_US
dc.relation.ispartofCell Death & Diseaseen
dc.subjectnon-transformed primary cellsen_US
dc.subjectTRAILen_US
dc.subjectapoptosisen_US
dc.subjectc-FLIPen_US
dc.subjectXIAPen_US
dc.subjectBcl-2en_US
dc.subjectLIGAND-INDUCED APOPTOSISen_US
dc.subjectRECEPTOR-MEDIATED APOPTOSISen_US
dc.subjectPROSTATE CARCINOMA-CELLSen_US
dc.subjectDEATH-RECEPTORen_US
dc.subjectCANCER-CELLSen_US
dc.subjectANTITUMOR-ACTIVITYen_US
dc.subjectCELLULAR FLIPen_US
dc.subjectIN-VITROen_US
dc.subjectINHIBITORen_US
dc.subjectPROTEINen_US
dc.titleResistance to TRAIL in non-transformed cells is due to multiple redundant pathwaysen_US
dc.typeArticleen_US
dc.date.updated2015-03-16T14:49:16Z
dc.identifier.doiARTN e702
dc.description.peer-reviewedpeer-reviewed
dc.contributor.funder|~|
dc.internal.rssid4920153
dc.local.contactAfshin Samali, Bioscience Research Building, North Campus, Nui Galway. 2440 Email: afshin.samali@nuigalway.ie
dc.local.copyrightcheckedYes
dc.local.versionPUBLISHED
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