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Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells
AKT is the frequently overexpressed and constitutively active kinase within NSCLC cells and recognized as a promising target for NSCLC treatment. However, AKT inhibition relieves the feedback inhibition of upstream receptor tyrosine kinases (RTKs) that may weaken the efficiency of AKT inhibitors. Pl...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126555/ https://www.ncbi.nlm.nih.gov/pubmed/27897231 http://dx.doi.org/10.1038/srep37997 |
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author | Li, Ting Chen, Xin Chen, Xiuping Ma, Dik Lung Leung, Chung Hang Lu, Jin Jian |
author_facet | Li, Ting Chen, Xin Chen, Xiuping Ma, Dik Lung Leung, Chung Hang Lu, Jin Jian |
author_sort | Li, Ting |
collection | PubMed |
description | AKT is the frequently overexpressed and constitutively active kinase within NSCLC cells and recognized as a promising target for NSCLC treatment. However, AKT inhibition relieves the feedback inhibition of upstream receptor tyrosine kinases (RTKs) that may weaken the efficiency of AKT inhibitors. Platycodin D (PD), isolated from widely-used traditional Chinese medicine Platycodonis Radix, is now found to remarkably enhance the anti-proliferative effect of AKT inhibitors. In this study, combinatorial activity of AKT inhibitor MK2206 and PD on cell proliferation, apoptosis and related signaling were disclosed. Long-term AKT inhibition induced up-regulation of RTKs, including EGFR and HER-2. Co-treatment of MK2206 with PD could abolish this feedback survival through decrease of EGFR, HER-2, and p-AKT, and profound inhibition of 4E-BP1, leading to an amplified anti-proliferative and apoptotic activity in NSCLC cells. Similarly, feedback activation in response to reduction of AKT expression by small interfering RNA (siRNA) was also blocked by PD and apoptotic effect was further enhanced. Thus, PD potentiated proliferative inhibition and apoptotic induction of both AKT inhibitor and siRNA. These findings also reveal the limitations of suppressing feedback-regulated pathways by monotherapy and establish a mechanistic rationale for a novel combination approach targeting AKT for the treatment of NSCLC. |
format | Online Article Text |
id | pubmed-5126555 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-51265552016-12-08 Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells Li, Ting Chen, Xin Chen, Xiuping Ma, Dik Lung Leung, Chung Hang Lu, Jin Jian Sci Rep Article AKT is the frequently overexpressed and constitutively active kinase within NSCLC cells and recognized as a promising target for NSCLC treatment. However, AKT inhibition relieves the feedback inhibition of upstream receptor tyrosine kinases (RTKs) that may weaken the efficiency of AKT inhibitors. Platycodin D (PD), isolated from widely-used traditional Chinese medicine Platycodonis Radix, is now found to remarkably enhance the anti-proliferative effect of AKT inhibitors. In this study, combinatorial activity of AKT inhibitor MK2206 and PD on cell proliferation, apoptosis and related signaling were disclosed. Long-term AKT inhibition induced up-regulation of RTKs, including EGFR and HER-2. Co-treatment of MK2206 with PD could abolish this feedback survival through decrease of EGFR, HER-2, and p-AKT, and profound inhibition of 4E-BP1, leading to an amplified anti-proliferative and apoptotic activity in NSCLC cells. Similarly, feedback activation in response to reduction of AKT expression by small interfering RNA (siRNA) was also blocked by PD and apoptotic effect was further enhanced. Thus, PD potentiated proliferative inhibition and apoptotic induction of both AKT inhibitor and siRNA. These findings also reveal the limitations of suppressing feedback-regulated pathways by monotherapy and establish a mechanistic rationale for a novel combination approach targeting AKT for the treatment of NSCLC. Nature Publishing Group 2016-11-29 /pmc/articles/PMC5126555/ /pubmed/27897231 http://dx.doi.org/10.1038/srep37997 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ 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 http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Li, Ting Chen, Xin Chen, Xiuping Ma, Dik Lung Leung, Chung Hang Lu, Jin Jian Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells |
title | Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells |
title_full | Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells |
title_fullStr | Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells |
title_full_unstemmed | Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells |
title_short | Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells |
title_sort | platycodin d potentiates proliferation inhibition and apoptosis induction upon akt inhibition via feedback blockade in non-small cell lung cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126555/ https://www.ncbi.nlm.nih.gov/pubmed/27897231 http://dx.doi.org/10.1038/srep37997 |
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