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Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells
Cytarabine (Ara-C) is a first line clinical therapeutic agent for treatment of acute myeloid leukemia (AML). However, this therapy is limited due to high rate of resistance and relapse. Recent research has revealed that the poor prognosis and resistance to Ara-C in AML were associated with its abnor...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302954/ https://www.ncbi.nlm.nih.gov/pubmed/27462781 http://dx.doi.org/10.18632/oncotarget.10796 |
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author | Li, Peng Diab, Sarah Yu, Mingfeng Adams, Julian Islam, Saiful Basnet, Sunita K.C. Albrecht, Hugo Milne, Robert Wang, Shudong |
author_facet | Li, Peng Diab, Sarah Yu, Mingfeng Adams, Julian Islam, Saiful Basnet, Sunita K.C. Albrecht, Hugo Milne, Robert Wang, Shudong |
author_sort | Li, Peng |
collection | PubMed |
description | Cytarabine (Ara-C) is a first line clinical therapeutic agent for treatment of acute myeloid leukemia (AML). However, this therapy is limited due to high rate of resistance and relapse. Recent research has revealed that the poor prognosis and resistance to Ara-C in AML were associated with its abnormally activated MAPK pathways. In this study, we showed a strong synergistic effect of Ara-C with either our Mnk inhibitor (MNKI-8e) or short hairpin RNA (shRNA) mediated knockdown of Mnks in MV4-11 AML cells. We investigated the underlying mechanisms for this synergism. We showed that both MNKI-8e and Mnk shRNAs enhanced the ability of Ara-C to induce apoptosis. We found that Ara-C increased the phosphorylation of Erk1/2, p38 and eIF4E, which correlated with an enhanced level of anti-apoptotic Mcl-1 protein. Inhibition of Mnk activity suppressed the Ara-C-induced MAPK activity, and thus enhanced apoptosis in MV4-11 cells. Taken together, our study suggests that MAPK-Mnk-eIF4E pathway plays a critical role in Ara-C-treated MV4-11 cells and targeting Mnk may be a promising therapeutic strategy for sensitizing leukemic cells to Ara-C therapy. |
format | Online Article Text |
id | pubmed-5302954 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53029542017-02-13 Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells Li, Peng Diab, Sarah Yu, Mingfeng Adams, Julian Islam, Saiful Basnet, Sunita K.C. Albrecht, Hugo Milne, Robert Wang, Shudong Oncotarget Research Paper Cytarabine (Ara-C) is a first line clinical therapeutic agent for treatment of acute myeloid leukemia (AML). However, this therapy is limited due to high rate of resistance and relapse. Recent research has revealed that the poor prognosis and resistance to Ara-C in AML were associated with its abnormally activated MAPK pathways. In this study, we showed a strong synergistic effect of Ara-C with either our Mnk inhibitor (MNKI-8e) or short hairpin RNA (shRNA) mediated knockdown of Mnks in MV4-11 AML cells. We investigated the underlying mechanisms for this synergism. We showed that both MNKI-8e and Mnk shRNAs enhanced the ability of Ara-C to induce apoptosis. We found that Ara-C increased the phosphorylation of Erk1/2, p38 and eIF4E, which correlated with an enhanced level of anti-apoptotic Mcl-1 protein. Inhibition of Mnk activity suppressed the Ara-C-induced MAPK activity, and thus enhanced apoptosis in MV4-11 cells. Taken together, our study suggests that MAPK-Mnk-eIF4E pathway plays a critical role in Ara-C-treated MV4-11 cells and targeting Mnk may be a promising therapeutic strategy for sensitizing leukemic cells to Ara-C therapy. Impact Journals LLC 2016-07-23 /pmc/articles/PMC5302954/ /pubmed/27462781 http://dx.doi.org/10.18632/oncotarget.10796 Text en Copyright: © 2016 Li et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Li, Peng Diab, Sarah Yu, Mingfeng Adams, Julian Islam, Saiful Basnet, Sunita K.C. Albrecht, Hugo Milne, Robert Wang, Shudong Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells |
title | Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells |
title_full | Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells |
title_fullStr | Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells |
title_full_unstemmed | Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells |
title_short | Inhibition of Mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells |
title_sort | inhibition of mnk enhances apoptotic activity of cytarabine in acute myeloid leukemia cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302954/ https://www.ncbi.nlm.nih.gov/pubmed/27462781 http://dx.doi.org/10.18632/oncotarget.10796 |
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