Activation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatin-resistant cancer cells.
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.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
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Seah
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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Low
Cancer Science Institute, National University Health System, Singapore.
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Hirpara
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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Sachaphibulkij
Equipe 11 Labellisée par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France.|INSERM, U1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
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Kroemer
INSERM UMR-S 1180, LaBex LERMIT, University of Paris Sud, Châtenay-Malabry, France.
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Brenner
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.|National University Cancer Institute, National University Health System, Singapore.|School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia.
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Pervaiz
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D021381:Protein Transport; D026361:Reactive Nitrogen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
D000970:Antineoplastic Agents; D026361:Reactive Nitrogen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D030421:Peroxynitrous Acid; D002945:Cisplatin