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dc.contributor.authorSeah, S.
dc.contributor.authorLow, It Meng
dc.contributor.authorHirpara, J.
dc.contributor.authorSachaphibulkij, K.
dc.contributor.authorKroemer, G.
dc.contributor.authorBrenner, C.
dc.contributor.authorPervaiz, Shazib
dc.date.accessioned2017-03-17T08:29:26Z
dc.date.available2017-03-17T08:29:26Z
dc.date.created2017-02-19T19:31:46Z
dc.date.issued2015
dc.date.submitted2017-02-20
dc.identifier.citationSeah, S. and Low, I. and Hirpara, J. and Sachaphibulkij, K. and Kroemer, G. and Brenner, C. and Pervaiz, S. 2015. Activation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatin-resistant cancer cells. Cell Death and Disease. 6: e1926.
dc.identifier.urihttp://hdl.handle.net/20.500.11937/51036
dc.identifier.doi10.1038/cddis.2015.299
dc.description.abstract

Platinum-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.

dc.publisherNature Publishing Group
dc.titleActivation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatin-resistant cancer cells
dc.typeJournal Article
dcterms.dateSubmitted2017-02-20
dcterms.source.volume6
dcterms.source.startPagee1926
dcterms.source.endPagee1926
dcterms.source.titleCell Death and Disease
curtin.digitool.pid248367
curtin.departmentSchool of Biomedical Sciences
curtin.identifier.elementsidELEMENTS-109484
curtin.accessStatusOpen access via publisher


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