Please use this identifier to cite or link to this item: https://doi.org/10.1038/cddis.2015.299
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dc.titleActivation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatinresistant cancer cells
dc.contributor.authorSeah, S
dc.contributor.authorLow, I
dc.contributor.authorHirpara, J.L
dc.contributor.authorSachaphibulkij, K
dc.contributor.authorKroemer, G
dc.contributor.authorBrenner, C
dc.contributor.authorPervaiz, S
dc.date.accessioned2020-09-10T01:50:22Z
dc.date.available2020-09-10T01:50:22Z
dc.date.issued2015
dc.identifier.citationSeah, S, Low, I, Hirpara, J.L, Sachaphibulkij, K, Kroemer, G, Brenner, C, Pervaiz, S (2015). Activation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatinresistant cancer cells. Cell Death and Disease 6 (10) : e1926. ScholarBank@NUS Repository. https://doi.org/10.1038/cddis.2015.299
dc.identifier.issn20414889
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/175479
dc.description.abstractPlatinum-based drugs remain as the cornerstone of cancer chemotherapy; however, development of multidrug resistance presents a therapeutic challenge. This study aims at understanding the molecular mechanisms underlying resistance to cisplatin and unraveling surrogate signaling networks that could revert sensitivity to apoptosis stimuli. We made use of three different sets of cell lines, A549 and H2030 non-small-cell lung cancer (NSCLC) and A2780 ovarian cancer cells and their cisplatin-resistant variants. Here we report that cisplatin-resistant cell lines displayed a multidrug-resistant phenotype. Changes in mitochondrial metabolism and defective mitochondrial signaling were unraveled in the resistant cells. More interestingly, a marked increase in sensitivity of the resistant cells to death receptor-induced apoptosis, in particular TRAIL (TNF-related apoptosis-inducing ligand)-mediated execution, was observed. Although this was not associated with an increase in gene transcription, a significant increase in the localization of TRAIL death receptor, DR4, to the lipid raft subdomains of plasma membrane was detected in the resistant variants. Furthermore, exposure of cisplatin-resistant cells to TRAIL resulted in upregulation of inducible nitric oxide synthase (iNOS) and increase in nitric oxide (NO) production that triggered the generation of peroxynitrite (ONOO- ). Scavenging ONOO- rescued cells from TRAIL-induced apoptosis, thereby suggesting a critical role of ONOO- in TRAIL-induced execution of cisplatin-resistant cells. Notably, preincubation of cells with TRAIL restored sensitivity of resistant cells to cisplatin. These data provide compelling evidence for employing strategies to trigger death receptor signaling as a second-line treatment for cisplatin-resistant cancers. © 2015 Macmillan Publishers Limited All rights reserved.
dc.publisherNature Publishing Group
dc.sourceUnpaywall 20200831
dc.subjectcisplatin
dc.subjectdeath receptor
dc.subjectinducible nitric oxide synthase
dc.subjectnitric oxide
dc.subjectperoxynitrite
dc.subjectreactive nitrogen species
dc.subjecttumor necrosis factor related apoptosis inducing ligand
dc.subjectantineoplastic agent
dc.subjectcisplatin
dc.subjectperoxynitrous acid
dc.subjectTNFRSF10A protein, human
dc.subjecttumor necrosis factor related apoptosis inducing ligand
dc.subjecttumor necrosis factor related apoptosis inducing ligand receptor
dc.subjecta2780 cell line
dc.subjectA549 cell line
dc.subjectapoptosis
dc.subjectArticle
dc.subjectcancer cell
dc.subjectcancer chemotherapy
dc.subjectcancer resistance
dc.subjectcell death
dc.subjectcell membrane
dc.subjectcross resistance
dc.subjectdisease association
dc.subjectDNA fragmentation
dc.subjectdrug potentiation
dc.subjectfemale
dc.subjectgenetic transcription
dc.subjecth2030 cell line
dc.subjecthuman
dc.subjecthuman cell
dc.subjectlipid raft
dc.subjectlung cancer cell line
dc.subjectmitochondrial respiration
dc.subjectnon small cell lung cancer
dc.subjectovarian cancer cell line
dc.subjectpriority journal
dc.subjectsignal transduction
dc.subjectupregulation
dc.subjectdrug effects
dc.subjectdrug resistance
dc.subjectmetabolism
dc.subjectprotein transport
dc.subjectsignal transduction
dc.subjecttumor cell line
dc.subjectAntineoplastic Agents
dc.subjectApoptosis
dc.subjectCell Line, Tumor
dc.subjectCisplatin
dc.subjectDrug Resistance, Neoplasm
dc.subjectDrug Synergism
dc.subjectHumans
dc.subjectMembrane Microdomains
dc.subjectPeroxynitrous Acid
dc.subjectProtein Transport
dc.subjectReactive Nitrogen Species
dc.subjectReceptors, TNF-Related Apoptosis-Inducing Ligand
dc.subjectSignal Transduction
dc.subjectTNF-Related Apoptosis-Inducing Ligand
dc.typeArticle
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.contributor.departmentDEPT OF PHYSIOLOGY
dc.description.doi10.1038/cddis.2015.299
dc.description.sourcetitleCell Death and Disease
dc.description.volume6
dc.description.issue10
dc.description.pagee1926
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