Activation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatin-resistant cancer cells
Identifieur interne : 001202 ( Pmc/Checkpoint ); précédent : 001201; suivant : 001203Activation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatin-resistant cancer cells
Auteurs : S. Seah [Singapour] ; I C C. Low [Singapour] ; J L Hirpara [Singapour] ; K. Sachaphibulkij [Singapour] ; G. Kroemer [France] ; C. Brenner [France] ; S. Pervaiz [Singapour, Australie]Source :
- Cell Death & Disease [ 2041-4889 ] ; 2015.
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.
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DOI: 10.1038/cddis.2015.299
PubMed: 26492363
PubMed Central: 4632318
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Seah</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Low, I C C" sort="Low, I C C" uniqKey="Low I" first="I C C" last="Low">I C C. Low</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hirpara, J L" sort="Hirpara, J L" uniqKey="Hirpara J" first="J L" last="Hirpara">J L Hirpara</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Cancer Science Institute, National University Health System</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sachaphibulkij, K" sort="Sachaphibulkij, K" uniqKey="Sachaphibulkij K" first="K" last="Sachaphibulkij">K. Sachaphibulkij</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G" last="Kroemer">G. 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Seah</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Low, I C C" sort="Low, I C C" uniqKey="Low I" first="I C C" last="Low">I C C. Low</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hirpara, J L" sort="Hirpara, J L" uniqKey="Hirpara J" first="J L" last="Hirpara">J L Hirpara</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Cancer Science Institute, National University Health System</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sachaphibulkij, K" sort="Sachaphibulkij, K" uniqKey="Sachaphibulkij K" first="K" last="Sachaphibulkij">K. Sachaphibulkij</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G" last="Kroemer">G. Kroemer</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Equipe 11 Labellisée par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center</institution>, Villejuif,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>INSERM, U1138</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Université Paris Descartes, Sorbonne Paris Cité</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff8"><institution>Université Pierre et Marie Curie</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP</institution>, Paris,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Brenner, C" sort="Brenner, C" uniqKey="Brenner C" first="C" last="Brenner">C. Brenner</name><affiliation wicri:level="1"><nlm:aff id="aff10"><institution>INSERM UMR-S 1180, LaBex LERMIT, University of Paris Sud</institution>, Châtenay-Malabry,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pervaiz, S" sort="Pervaiz, S" uniqKey="Pervaiz S" first="S" last="Pervaiz">S. Pervaiz</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff11"><institution>National University Cancer Institute, National University Health System</institution>,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff12"><institution>School of Biomedical Sciences, Curtin University</institution>, Perth, Western Australia,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Cell Death & Disease</title><idno type="eISSN">2041-4889</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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<sup>−</sup>). Scavenging ONOO<sup>−</sup> rescued cells from TRAIL-induced apoptosis, thereby suggesting a critical role of ONOO<sup>−</sup> 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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Death Dis</journal-id><journal-id journal-id-type="iso-abbrev">Cell Death Dis</journal-id><journal-title-group><journal-title>Cell Death & Disease</journal-title></journal-title-group><issn pub-type="epub">2041-4889</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26492363</article-id><article-id pub-id-type="pmc">4632318</article-id><article-id pub-id-type="pii">cddis2015299</article-id><article-id pub-id-type="doi">10.1038/cddis.2015.299</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Activation of surrogate death receptor signaling triggers peroxynitrite-dependent execution of cisplatin-resistant cancer cells</article-title><alt-title alt-title-type="running">TRAIL signaling in cisplatin-resistant cells</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Seah</surname><given-names>S</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Low</surname><given-names>I C C</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hirpara</surname><given-names>J L</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Sachaphibulkij</surname><given-names>K</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kroemer</surname><given-names>G</given-names></name><xref ref-type="aff" rid="aff4">4</xref><xref ref-type="aff" rid="aff5">5</xref><xref ref-type="aff" rid="aff6">6</xref><xref ref-type="aff" rid="aff7">7</xref><xref ref-type="aff" rid="aff8">8</xref><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Brenner</surname><given-names>C</given-names></name><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Pervaiz</surname><given-names>S</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff11">11</xref><xref ref-type="aff" rid="aff12">12</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><aff id="aff1"><label>1</label><institution>Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore</institution>,<country>Singapore</country></aff><aff id="aff2"><label>2</label><institution>NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore</institution>,<country>Singapore</country></aff><aff id="aff3"><label>3</label><institution>Cancer Science Institute, National University Health System</institution>,<country>Singapore</country></aff><aff id="aff4"><label>4</label><institution>Equipe 11 Labellisée par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers</institution>, Paris,<country>France</country></aff><aff id="aff5"><label>5</label><institution>Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center</institution>, Villejuif,<country>France</country></aff><aff id="aff6"><label>6</label><institution>INSERM, U1138</institution>, Paris,<country>France</country></aff><aff id="aff7"><label>7</label><institution>Université Paris Descartes, Sorbonne Paris Cité</institution>, Paris,<country>France</country></aff><aff id="aff8"><label>8</label><institution>Université Pierre et Marie Curie</institution>, Paris,<country>France</country></aff><aff id="aff9"><label>9</label><institution>Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP</institution>, Paris,<country>France</country></aff><aff id="aff10"><label>10</label><institution>INSERM UMR-S 1180, LaBex LERMIT, University of Paris Sud</institution>, Châtenay-Malabry,<country>France</country></aff><aff id="aff11"><label>11</label><institution>National University Cancer Institute, National University Health System</institution>,<country>Singapore</country></aff><aff id="aff12"><label>12</label><institution>School of Biomedical Sciences, Curtin University</institution>, Perth, Western Australia,<country>Australia</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label><institution>Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive</institution>, Building MD9 Level 4, Singapore 117597, <country>Singapore</country>. Tel: +65 65166602; Fax: +65 67788161; E-mail: <email>Shazib_Pervaiz@nuhs.edu.sg</email></corresp></author-notes><pub-date pub-type="ppub"><month>10</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>22</day><month>10</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>1</day><month>10</month><year>2015</year></pub-date><volume>6</volume><issue>10</issue><fpage>e1926</fpage><lpage></lpage><history><date date-type="received"><day>15</day><month>04</month><year>2015</year></date><date date-type="rev-recd"><day>14</day><month>09</month><year>2015</year></date><date date-type="accepted"><day>15</day><month>09</month><year>2015</year></date></history><permissions><copyright-statement>Copyright © 2015 Macmillan Publishers Limited</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>Macmillan Publishers Limited</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p><italic>Cell Death and Disease</italic> is an open-access journal published by <italic>Nature Publishing Group</italic>. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>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<sup>−</sup>). Scavenging ONOO<sup>−</sup> rescued cells from TRAIL-induced apoptosis, thereby suggesting a critical role of ONOO<sup>−</sup> 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.</p></abstract></article-meta></front><floats-group><fig id="fig1"><label>Figure 1</label><caption><p>Sensitivity of A549 WT, R1 and R2 cells to platinum-based drugs. Cells were treated with (<bold>a</bold>) cisplatin (<italic>μ</italic>M) or (<bold>b</bold>) carboplatin (mM) at the indicated doses for 24 h and cell viability was assessed by MTT assay. <italic>P</italic><0.01 compared with WT treated at respective dose. (<bold>c</bold>) WT, R1 and R2 cells were treated with various concentrations of cisplatin for 24, 48 and 72 h. Cell viability was determined by MTT assay and expressed as % of untreated control. (<bold>d</bold>) Cells were treated with increasing doses of cisplatin for 24 h and DNA content was analyzed by flow cytometry after staining with propidium iodide (PI); y axis: events, x axis: PI linear fluorescence, <italic>n</italic>=3. (<bold>e</bold>) WT, R1 and R2 cells were treated with the indicated doses of cisplatin for 24 h and caspase 3, 8 or 9 processing and PARP cleavage was determined by western blotting. Data shown are mean±S.D. of at least three independent experiments. In panels <bold>a</bold> and <bold>b</bold>: ** and <sup>##</sup> indicate <italic>P</italic>-value<0.005 compared to cisplatin sensitivity of WT cells. In panel <bold>c</bold>: * and ** indicate <italic>P</italic>-value<0.05 compared to WT cells treated with cisplatin for 48 and 72h, respectively</p></caption><graphic xlink:href="cddis2015299f1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Cisplatin-resistant cells exhibit cross-resistance to DNA-damaging agents but not death-receptor signaling. A549 WT and the cisplatin-resistant cells were treated with (<bold>a</bold>) 5-fluorouracil (<italic>μ</italic>M), (<bold>b</bold>) etoposide (<italic>μ</italic>M), (<bold>c</bold>) gemcitabine (mM), (<bold>d</bold>) TRAIL (ng/ml) or (<bold>e</bold>) Fas activating antibody (<italic>μ</italic>g/ml) at the indicated doses for 24 h. Cell viability was determined by MTT assay and expressed as % of untreated control. *<sup>,#</sup><italic>P</italic><0.05 and **<sup>,##</sup><italic>P</italic><0.005 compared with WT treated at respective dose. (<bold>f</bold>) Western blot analysis of various proteins important in regulating mitochondria-mediated apoptotic signaling. β-Actin was used as a loading control. (<bold>g</bold>) Oxygen consumption of WT and R1 cells were assessed using a Clark electrode. State 3 respiration was initiated with addition of exogenous 0.2 mM ADP (arrow). The slope of the curve is a measure of the rate of oxygen consumption for a period of 20 min. Respiratory ETC complex I (<bold>h)</bold>, II (<bold>i)</bold> and IV (<bold>j</bold>) activities were measured in WT and R1 cells using the 96-well enzymatic-based microplate assay kit. *<italic>P</italic><0.05 and **<italic>P</italic><0.005 compared with WT control. ΔmOD indicates change in maximum OD at 340nm. Data shown are mean±S.D. of at least three independent experiments</p></caption><graphic xlink:href="cddis2015299f2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>TRAIL induces caspase-dependent apoptosis in cisplatin-resistant cells. (<bold>a</bold>) Cell cycle analysis. Cells (A549 WT, R1 and R2) were treated with increasing doses of TRAIL for 4 h and DNA content was analyzed by flow cytometry after staining with propidium iodide (PI); y axis: events, x axis: PI linear fluorescence. (<bold>b</bold>) A549 WT and R1 cells were treated with the indicated doses of TRAIL in a time-dependent manner. Western blotting for caspase 3 and caspase 8 processing as well as PARP cleavage was performed using GAPDH as the loading control. (<bold>c</bold>) Cisplatin-resistant R1 cells were preincubated with ZVAD-fmk (50 <italic>μ</italic>M) for 1 h followed by 24 h of treatment with 50 ng/ml of TRAIL. Whole-cell lysates were subjected to western blotting for caspase 3 and caspase 8 processing as well as PARP cleavage. GAPDH was used as loading control. (<bold>d</bold>) R1 cells were treated with 50 or 100 ng/ml of TRAIL in the presence or absence of 50 <italic>μ</italic>M ZVAD-fmk and cell viability was measured by MTT assay and expressed as % of untreated cells. Data shown are mean±S.D. of at least three independent experiments. *<italic>P</italic>-value<0.05 compared to cells treated with TRAIL alone</p></caption><graphic xlink:href="cddis2015299f3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>DR4 is redistributed to lipid raft subdomains in R1 cells. (<bold>a</bold>) Western blot analysis for various proteins important in regulating the extrinsic apoptotic pathway. GAPDH was used as loading control. (<bold>b</bold>) R1 cells were preincubated with soluble monoclonal antibodies against DR4 or DR5 (<italic>μ</italic>g) for 1 h followed by 24 h of treatment with 50 ng/ml of TRAIL. Cell viability was determined by MTT assay and expressed as % of untreated control. (<bold>c</bold>) R1 cells were transiently transfected with either scrambled siRNA or siRNA against DR4 or DR5 for 48 h followed by 50 ng/ml of TRAIL treatment for 24 h and cell viability were determined using MTT assay; *<italic>P</italic><0.05. (<bold>d</bold>) R1 cells were preincubated with blocking antibodies against DR4 and DR5 for 1 h followed by 24 h of treatment with 50 ng/ml of TRAIL and lysates were subjected to western blot analysis for the assessment of caspase 3 and caspase 8 processing as well as PARP cleavage. (<bold>e</bold>) WT (top) and R1 cells (bottom) were treated with 50 ng/ml TRAIL for 15 min and subjected to discontinuous sucrose density gradients of Triton X-100 cell lysates for separation of lipid raft and non-raft fractions. One to 9 fractions were examined by western blots for the presence of DR4 and DR5 (first two rows). Lipid raft fractions 5 and 6 were identified by western blots. Flotillin and caveolin-1 were used as lipid raft markers. (<bold>f</bold>) Following TRAIL (50 ng/ml) treatment for 15 min, WT and R1 cells were subjected to discontinuous sucrose density gradients of Triton X-100 cell lysates for separation of lipid raft and nonraft fractions. Fractions 4–6 were collected and immunoprecipitated with anti-caveolin-1 antibody. As shown, caveolin-1 and FADD protein expression were detected by immunoblotting. (<bold>g</bold>) R1 cells were preincubated with the indicated doses of MCD for 1 h followed by 24 h of treatment with 50 ng/ml of TRAIL. Whole-cell lysates were subjected to western blot analysis for the assessment of caspase 3 and caspase 8 processing as well as PARP cleavage. GAPDH was used as loading control. Data shown are mean±S.D. of at least three independent experiments</p></caption><graphic xlink:href="cddis2015299f4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>TRAIL-induced cell death in R1 cells involves the generation of reactive nitrogen species. (<bold>a</bold>) WT and R1 cells were treated with 50 ng/ml of TRAIL for 2 and 4 h. Cells were subsequently harvested and analyzed by flow cytometry for ROS production using redox-sensitive probe DCFH-DA. (<bold>b</bold>) R1 cells were preincubated with 50 <italic>μ</italic>M FeTPPs for 1 h followed by 50 ng/ml of TRAIL for 2 or 4 h. Cells were subsequently harvested and analyzed by flow cytometry after loading with DCFH-DA. (<bold>c</bold>) Cells were treated as above and loaded with NO-specific probe DAF or (<bold>d</bold>) MitoSox before flow cytomteric analysis. Antimycin A (AA) was used as a positive control for mitochondrial O<sub>2</sub><sup>−</sup>. Data are shown as mean±S.D. of fold differences of fluorescence from untreated cells for at least three independent experiments. (<bold>e</bold>) Western blot analysis of iNOS following treatment of WT and R1 cells with 50 and 100 ng/ml of TRAIL. (<bold>f</bold>) R1 cells were preincubated with FeTPPs (50 <italic>μ</italic>M) for 1 h followed by 24 h of treatment with 50 ng/ml of TRAIL. Cell viability was determined by MTT assay and expressed as % of untreated control cells. *<italic>P</italic><0.05 compared with 50 ng/ml of TRAIL alone and <sup>#</sup><italic>P</italic><0.05 compared with 100 ng/ml of TRAIL alone. Data shown are mean±S.D. of at least three independent experiments. (<bold>g</bold>) Western blot analysis of iNOS in R1 cells, pretreated with 50 <italic>μ</italic>M ZVAD for 1 h followed by 50 ng/ml of TRAIL for 8 h. (<bold>h</bold>) WT and R1 cells were pretreated with 50 <italic>μ</italic>M ZVAD for 1 h followed by 50 ng/ml of TRAIL for 2 and 4 h. Cells were harvested and analyzed by flow cytometry for intracellular ROS production with DCFH-DA. Data shown are representative of at least three independent experiments. (<bold>i</bold>) R1 cells were preincubated with FeTPPs for 1 h followed by 24 h of treatment with 50 ng/ml of TRAIL and whole-cell lysates were subjected to western blot analysis for the assessment of caspase 3 and 8 processing as well as PARP cleavage. GAPDH was used as loading control</p></caption><graphic xlink:href="cddis2015299f5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>TRAIL exposure restores apoptosis sensitivity of cisplatin-resistant (CR) cells. (<bold>a</bold>) A549 R1, (<bold>b</bold>) H2030 CR and (<bold>c</bold>) A2780 CR cells were pretreated with varying doses of TRAIL for 2 h and followed with the indicated doses of cisplatin for 24 h. Cell viability was assessed by MTT and expressed as % of untreated control cells. Data shown are mean±S.D. of at least three independent experiments. Concurrently, the cell lysates from (<bold>d</bold>) A549 R1, (<bold>e</bold>) H2030 CR and (<bold>f</bold>) A2780 CR were collected to assay for caspase 3 and caspase 8 processing as well as PARP cleavage by western blot analysis. GAPDH was used as loading control. *, #, Δ indicated <italic>P</italic>-Value<0.05 compared to cells treated with cisplatin alone</p></caption><graphic xlink:href="cddis2015299f6"></graphic></fig><fig id="fig7"><label>Figure 7</label><caption><p>Schematic diagram of TRAIL sensitivity in WT and cisplatin-resistant cancer cells: in the WT cells, TRAIL receptors exist as monomers and upon TRAIL ligation, the receptors oligomerize to form the DISC and subsequently activation of pro-caspase 8. However, because of overexpression of anti-apoptotic proteins such as cFLIP, XIAP and cIAP2, apoptotic execution is imparied. In R1 cells, TRAIL receptors are redistributed to the lipid raft subdomian, and hence are ‘primed' for rapid activation. Upon ligation, the apoptotic signals are transduced promptly that involves downregulation of anti-apoptotic proteins as well as induction of an amplification signal via OONO<sup>−</sup> formation for efficient death execution</p></caption><graphic xlink:href="cddis2015299f7"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Australie</li><li>France</li><li>Singapour</li></country></list><tree><country name="Singapour"><noRegion><name sortKey="Seah, S" sort="Seah, S" uniqKey="Seah S" first="S" last="Seah">S. Seah</name></noRegion><name sortKey="Hirpara, J L" sort="Hirpara, J L" uniqKey="Hirpara J" first="J L" last="Hirpara">J L Hirpara</name><name sortKey="Low, I C C" sort="Low, I C C" uniqKey="Low I" first="I C C" last="Low">I C C. Low</name><name sortKey="Pervaiz, S" sort="Pervaiz, S" uniqKey="Pervaiz S" first="S" last="Pervaiz">S. Pervaiz</name><name sortKey="Pervaiz, S" sort="Pervaiz, S" uniqKey="Pervaiz S" first="S" last="Pervaiz">S. Pervaiz</name><name sortKey="Pervaiz, S" sort="Pervaiz, S" uniqKey="Pervaiz S" first="S" last="Pervaiz">S. Pervaiz</name><name sortKey="Sachaphibulkij, K" sort="Sachaphibulkij, K" uniqKey="Sachaphibulkij K" first="K" last="Sachaphibulkij">K. Sachaphibulkij</name><name sortKey="Seah, S" sort="Seah, S" uniqKey="Seah S" first="S" last="Seah">S. Seah</name></country><country name="France"><noRegion><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G" last="Kroemer">G. Kroemer</name></noRegion><name sortKey="Brenner, C" sort="Brenner, C" uniqKey="Brenner C" first="C" last="Brenner">C. Brenner</name><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G" last="Kroemer">G. Kroemer</name><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G" last="Kroemer">G. Kroemer</name><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G" last="Kroemer">G. Kroemer</name><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G" last="Kroemer">G. Kroemer</name><name sortKey="Kroemer, G" sort="Kroemer, G" uniqKey="Kroemer G" first="G" last="Kroemer">G. Kroemer</name></country><country name="Australie"><noRegion><name sortKey="Pervaiz, S" sort="Pervaiz, S" uniqKey="Pervaiz S" first="S" last="Pervaiz">S. Pervaiz</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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