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CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway

The mammalian target of rapamycin (mTOR) is a potentially important therapeutic target in a broad range of cancer types. mTOR inhibitors such as rapamycin and its analogs (rapalogs) have been proven effective as anticancer agents in non-small cell lung cancer (NSCLC), whereas they strongly enhance p...

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Autores principales: Wen, Qiuyuan, Wang, Weiyuan, Luo, Jiadi, Chu, Shuzhou, Chen, Lingjiao, Xu, Lina, Zang, Hongjing, Alnemah, Mohannad Ma, Ma, Jian, Fan, Songqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053688/
https://www.ncbi.nlm.nih.gov/pubmed/27050281
http://dx.doi.org/10.18632/oncotarget.8497
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author Wen, Qiuyuan
Wang, Weiyuan
Luo, Jiadi
Chu, Shuzhou
Chen, Lingjiao
Xu, Lina
Zang, Hongjing
Alnemah, Mohannad Ma
Ma, Jian
Fan, Songqing
author_facet Wen, Qiuyuan
Wang, Weiyuan
Luo, Jiadi
Chu, Shuzhou
Chen, Lingjiao
Xu, Lina
Zang, Hongjing
Alnemah, Mohannad Ma
Ma, Jian
Fan, Songqing
author_sort Wen, Qiuyuan
collection PubMed
description The mammalian target of rapamycin (mTOR) is a potentially important therapeutic target in a broad range of cancer types. mTOR inhibitors such as rapamycin and its analogs (rapalogs) have been proven effective as anticancer agents in non-small cell lung cancer (NSCLC), whereas they strongly enhance phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and activation of Akt, which cause resistance to mTOR-targeted therapy after an initial response. Rapamycin induces eIF4E phosphorylation by activating MAPK-interacting kinases (Mnks), and therefore targeting Mnk/eIF4E pathway represents a potential therapeutic strategy for the treatment of NSCLC. Here, our results showed that over-expression of p-Mnk1 and p-eIF4E was significantly associated with poor overall survival of NSCLC patients and high expression of p-Mnk1 might act as an independent prognostic biomarker for these patients. Meanwhile, inhibiting Mnk1 expression by Mnk inhibitor (CGP57380) could abrogate rapalogs (RAD001)-induced eIF4E phosphorylation and Akt activation. Furthermore, combination of CGP57380 and RAD001 could induce NSCLC cells apoptosis via activating intrinsic mitochondrial pathway, and exert synergistic antitumor efficacy both in vitro and in vivo. In conclusion, combination of targeting both mTOR and Mnk/eIF4E signaling pathways to enhance effectiveness of mTOR-targeted cancer therapy might be significant innovation for the personalized treatment of NSCLC.
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spelling pubmed-50536882016-10-12 CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway Wen, Qiuyuan Wang, Weiyuan Luo, Jiadi Chu, Shuzhou Chen, Lingjiao Xu, Lina Zang, Hongjing Alnemah, Mohannad Ma Ma, Jian Fan, Songqing Oncotarget Research Paper The mammalian target of rapamycin (mTOR) is a potentially important therapeutic target in a broad range of cancer types. mTOR inhibitors such as rapamycin and its analogs (rapalogs) have been proven effective as anticancer agents in non-small cell lung cancer (NSCLC), whereas they strongly enhance phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and activation of Akt, which cause resistance to mTOR-targeted therapy after an initial response. Rapamycin induces eIF4E phosphorylation by activating MAPK-interacting kinases (Mnks), and therefore targeting Mnk/eIF4E pathway represents a potential therapeutic strategy for the treatment of NSCLC. Here, our results showed that over-expression of p-Mnk1 and p-eIF4E was significantly associated with poor overall survival of NSCLC patients and high expression of p-Mnk1 might act as an independent prognostic biomarker for these patients. Meanwhile, inhibiting Mnk1 expression by Mnk inhibitor (CGP57380) could abrogate rapalogs (RAD001)-induced eIF4E phosphorylation and Akt activation. Furthermore, combination of CGP57380 and RAD001 could induce NSCLC cells apoptosis via activating intrinsic mitochondrial pathway, and exert synergistic antitumor efficacy both in vitro and in vivo. In conclusion, combination of targeting both mTOR and Mnk/eIF4E signaling pathways to enhance effectiveness of mTOR-targeted cancer therapy might be significant innovation for the personalized treatment of NSCLC. Impact Journals LLC 2016-03-30 /pmc/articles/PMC5053688/ /pubmed/27050281 http://dx.doi.org/10.18632/oncotarget.8497 Text en Copyright: © 2016 Wen 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
Wen, Qiuyuan
Wang, Weiyuan
Luo, Jiadi
Chu, Shuzhou
Chen, Lingjiao
Xu, Lina
Zang, Hongjing
Alnemah, Mohannad Ma
Ma, Jian
Fan, Songqing
CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway
title CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway
title_full CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway
title_fullStr CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway
title_full_unstemmed CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway
title_short CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway
title_sort cgp57380 enhances efficacy of rad001 in non-small cell lung cancer through abrogating mtor inhibition-induced phosphorylation of eif4e and activating mitochondrial apoptotic pathway
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053688/
https://www.ncbi.nlm.nih.gov/pubmed/27050281
http://dx.doi.org/10.18632/oncotarget.8497
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