title: Resistance to TRAIL in non-transformed cells is due to multiple redundant pathways.
abstract: Tumour 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 (≥1.2-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.
authors.affiliation: Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: M
authors.initials: M
authors.lastname: van Dijk
authors.forename: A
authors.initials: A
authors.lastname: Halpin-McCormick
authors.forename: T
authors.initials: T
authors.lastname: Sessler
authors.forename: A
authors.initials: A
authors.lastname: Samali
authors.forename: E
authors.initials: E
authors.lastname: Szegezdi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D015398:Signal Transduction; D012867:Skin / Q000166:cytology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D058851:GPI-Linked Proteins; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C108661:TNFRSF10C protein, human; C451501:TNFRSF10D protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003513:Cycloheximide; C505407:CASP3 protein, human; D053148:Caspase 3