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Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca(2+)/calmodulin signaling
TNF-related apoptosis-inducing ligand (TRAIL) is a promising cytokine for killing tumor cells. However, a number of studies have demonstrated that different cancer cells resist TRAIL treatment and, moreover, TRAIL can promote invasion and metastasis in resistant cells. Here we report that TRAIL rapi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613829/ https://www.ncbi.nlm.nih.gov/pubmed/23470529 http://dx.doi.org/10.1038/cddis.2013.51 |
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author | Kaminskyy, V O Surova, O V Piskunova, T Zborovskaya, I B Tchevkina, E M Andera, L Zhivotovsky, B |
author_facet | Kaminskyy, V O Surova, O V Piskunova, T Zborovskaya, I B Tchevkina, E M Andera, L Zhivotovsky, B |
author_sort | Kaminskyy, V O |
collection | PubMed |
description | TNF-related apoptosis-inducing ligand (TRAIL) is a promising cytokine for killing tumor cells. However, a number of studies have demonstrated that different cancer cells resist TRAIL treatment and, moreover, TRAIL can promote invasion and metastasis in resistant cells. Here we report that TRAIL rapidly activates caspase-8 in a panel of non-small-cell lung carcinomas (NSCLCs). Adenocarcinomas derived from the lung in addition to high caspase-8 expression are characterized by increased expression of DR4 compared with adjacent non-neoplastic tissues. Blocking DR4 or lowering caspase-8 expression significantly reduced apoptosis in NSCLC cell lines, indicating the importance of DR4 and signifying that higher levels of caspase-8 in lung adenocarcinomas make them more susceptible to TRAIL treatment. Despite rapid and robust initial responsiveness to TRAIL, surviving cells quickly acquired resistance to the additional TRAIL treatment. The expression of cellular-FLIP-short (c-FLIP(S)) was significantly increased in surviving cells. Such upregulation of c-FLIP(S) was rapidly reduced and TRAIL sensitivity was restored by treatment with cycloheximide. Silencing of c-FLIP(S), but not c-FLIP-long (c-FLIP(L)), resulted in a remarkable increase in apoptosis and significant reduction of clonogenic survival. Furthermore, chelation of intracellular Ca(2+) or inhibition of calmodulin caused a rapid proteasomal degradation of c-FLIP(S), a significant increase of the two-step processing of procaspase-8, and reduced clonogenicity in response to TRAIL. Thus, our results revealed that the upregulation of DR4 and caspase-8 expression in NSCLC cells make them more susceptible to TRAIL. However, these cells could survive TRAIL treatment via upregulation of c-FLIP(S), and it is suggested that blocking c-FLIP(S) expression by inhibition of Ca(2+)/calmodulin signaling significantly overcomes the acquired resistance of NSCLC cells to TRAIL. |
format | Online Article Text |
id | pubmed-3613829 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-36138292013-04-11 Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca(2+)/calmodulin signaling Kaminskyy, V O Surova, O V Piskunova, T Zborovskaya, I B Tchevkina, E M Andera, L Zhivotovsky, B Cell Death Dis Original Article TNF-related apoptosis-inducing ligand (TRAIL) is a promising cytokine for killing tumor cells. However, a number of studies have demonstrated that different cancer cells resist TRAIL treatment and, moreover, TRAIL can promote invasion and metastasis in resistant cells. Here we report that TRAIL rapidly activates caspase-8 in a panel of non-small-cell lung carcinomas (NSCLCs). Adenocarcinomas derived from the lung in addition to high caspase-8 expression are characterized by increased expression of DR4 compared with adjacent non-neoplastic tissues. Blocking DR4 or lowering caspase-8 expression significantly reduced apoptosis in NSCLC cell lines, indicating the importance of DR4 and signifying that higher levels of caspase-8 in lung adenocarcinomas make them more susceptible to TRAIL treatment. Despite rapid and robust initial responsiveness to TRAIL, surviving cells quickly acquired resistance to the additional TRAIL treatment. The expression of cellular-FLIP-short (c-FLIP(S)) was significantly increased in surviving cells. Such upregulation of c-FLIP(S) was rapidly reduced and TRAIL sensitivity was restored by treatment with cycloheximide. Silencing of c-FLIP(S), but not c-FLIP-long (c-FLIP(L)), resulted in a remarkable increase in apoptosis and significant reduction of clonogenic survival. Furthermore, chelation of intracellular Ca(2+) or inhibition of calmodulin caused a rapid proteasomal degradation of c-FLIP(S), a significant increase of the two-step processing of procaspase-8, and reduced clonogenicity in response to TRAIL. Thus, our results revealed that the upregulation of DR4 and caspase-8 expression in NSCLC cells make them more susceptible to TRAIL. However, these cells could survive TRAIL treatment via upregulation of c-FLIP(S), and it is suggested that blocking c-FLIP(S) expression by inhibition of Ca(2+)/calmodulin signaling significantly overcomes the acquired resistance of NSCLC cells to TRAIL. Nature Publishing Group 2013-03 2013-03-07 /pmc/articles/PMC3613829/ /pubmed/23470529 http://dx.doi.org/10.1038/cddis.2013.51 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Original Article Kaminskyy, V O Surova, O V Piskunova, T Zborovskaya, I B Tchevkina, E M Andera, L Zhivotovsky, B Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca(2+)/calmodulin signaling |
title | Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca(2+)/calmodulin signaling |
title_full | Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca(2+)/calmodulin signaling |
title_fullStr | Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca(2+)/calmodulin signaling |
title_full_unstemmed | Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca(2+)/calmodulin signaling |
title_short | Upregulation of c-FLIP-short in response to TRAIL promotes survival of NSCLC cells, which could be suppressed by inhibition of Ca(2+)/calmodulin signaling |
title_sort | upregulation of c-flip-short in response to trail promotes survival of nsclc cells, which could be suppressed by inhibition of ca(2+)/calmodulin signaling |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613829/ https://www.ncbi.nlm.nih.gov/pubmed/23470529 http://dx.doi.org/10.1038/cddis.2013.51 |
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