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Title: Activation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatinresistant cancer cells
Authors: Seah, S 
Low, I 
Hirpara, J.L 
Sachaphibulkij, K 
Kroemer, G
Brenner, C
Pervaiz, S 
Keywords: cisplatin
death receptor
inducible nitric oxide synthase
nitric oxide
reactive nitrogen species
tumor necrosis factor related apoptosis inducing ligand
antineoplastic agent
peroxynitrous acid
TNFRSF10A protein, human
tumor necrosis factor related apoptosis inducing ligand
tumor necrosis factor related apoptosis inducing ligand receptor
a2780 cell line
A549 cell line
cancer cell
cancer chemotherapy
cancer resistance
cell death
cell membrane
cross resistance
disease association
DNA fragmentation
drug potentiation
genetic transcription
h2030 cell line
human cell
lipid raft
lung cancer cell line
mitochondrial respiration
non small cell lung cancer
ovarian cancer cell line
priority journal
signal transduction
drug effects
drug resistance
protein transport
signal transduction
tumor cell line
Antineoplastic Agents
Cell Line, Tumor
Drug Resistance, Neoplasm
Drug Synergism
Membrane Microdomains
Peroxynitrous Acid
Protein Transport
Reactive Nitrogen Species
Receptors, TNF-Related Apoptosis-Inducing Ligand
Signal Transduction
TNF-Related Apoptosis-Inducing Ligand
Issue Date: 2015
Publisher: Nature Publishing Group
Citation: Seah, 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.
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. © 2015 Macmillan Publishers Limited All rights reserved.
Source Title: Cell Death and Disease
ISSN: 20414889
DOI: 10.1038/cddis.2015.299
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