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http://hdl.handle.net/10261/82326
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dc.contributor.author | Cortés-Sempere, María | - |
dc.contributor.author | Rodriguez-Fanjul, V. | - |
dc.contributor.author | Belda-Iniesta, Cristobal | - |
dc.contributor.author | Cejas, Paloma | - |
dc.contributor.author | Machado-Pinilla, R. | - |
dc.contributor.author | Manguan-García, Cristina | - |
dc.contributor.author | Sánchez-Pérez, Isabel | - |
dc.contributor.author | Nistal, Manuel | - |
dc.contributor.author | Moratilla, Carmen | - |
dc.contributor.author | Castro Carpeño, Javier de | - |
dc.contributor.author | González Barón, Manuel | - |
dc.contributor.author | Albanell, Joan | - |
dc.contributor.author | Perona Abellón, Rosario | - |
dc.date.accessioned | 2013-09-18T11:27:11Z | - |
dc.date.available | 2013-09-18T11:27:11Z | - |
dc.date.issued | 2009 | - |
dc.identifier | doi: 10.1016/j.canlet.2009.05.029 | - |
dc.identifier | issn: 0304-3835 | - |
dc.identifier | e-issn: 1872-7980 | - |
dc.identifier.citation | Cancer Letters 286(2): 206-216 (2009) | - |
dc.identifier.uri | http://hdl.handle.net/10261/82326 | - |
dc.description.abstract | Treatment of non-small cell lung cancer (NSCLC) with cisplatin has a level of antitumor activity still modest. We have shown previously that MKP1/DUSP1 inhibits cisplatin-induced apoptosis in NSCLC cells and is overexpressed in tumors from most patients with stage I–II NSCLC. Here, using different NSCLC cell lines we found that MKP1 and NF-κB are differentially expressed. We studied whether targeting MKP1, NF-κB or both affects cisplatin-induced cell death. MKP1 is expressed in H460 and H727 cells. H727 and H1299 cells showed constitutive phosphorylation of Akt and increased NF-κB activity than did H460 cells. H460-MKP1-siRNA-expressing cells (but not H727-MKP1-siRNA or H1299-MKP1-siRNA cells) exhibit a marked increase in cisplatin response compared with parental cells. Treatment with the PI3K inhibitor LY294002 or the NF-κB inhibitor BAY11-7082 enhanced cisplatin antitumor activity in parental H1299 cells but only weakly affected responses of H727 and H460 cells. MKP1-siRNA expression enhanced the chemosensitization effect of LY294002 and BAY11-7082 on H727 and H460 cells. Additionally, NSCLC cell lines with higher NF-κB-constitutive activation were the most sensitive to PS-341 (Bortezomib), a non-specific NF-κB inhibitor. This finding suggests the proteasome as a suitable strategy in treating NSCLC tumors with high constitutive NF-κB activity. Altogether, these results showed that either an activated PI3K/Akt/NF-κB pathway and/or high MKP1 was linked to reduced sensitivity to cisplatin in NSCLC cells. Inhibition of NF-κB or PI3K potently enhanced cisplatin cytotoxicity in cells with endogenous or genetically induced low MKP1 levels. These findings support the potential improvement in cisplatin responses by co-targeting NF-κB or Akt and MKP1. | - |
dc.description.sponsorship | This work was supported by Grants PI051305 (R.P), PI081485 (R.P.), PI061513 (J.A., A.R.), PI052019 (A.R) Grants and RETICS RD06/0020/0109 (J.A., A.R.) from the “Fondo de Investigación Sanitaria FIS/ISCIII ISCIII)” and from Fundación Mutua Madrileña. | - |
dc.language.iso | eng | - |
dc.publisher | Elsevier | - |
dc.rights | closedAccess | - |
dc.title | MKP1 repression is required for the chemosensitizing effects of NF-κB and PI3K inhibitors to cisplatin in non-small cell lung cancer | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1016/j.canlet.2009.05.029 | - |
dc.date.updated | 2013-09-18T11:27:11Z | - |
dc.description.version | Peer Reviewed | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.openairetype | artículo | - |
item.grantfulltext | none | - |
item.cerifentitytype | Publications | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.fulltext | No Fulltext | - |
item.languageiso639-1 | en | - |
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