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Asperolide A, a Marine-Derived Tetranorditerpenoid, Induces G2/M Arrest in Human NCI-H460 Lung Carcinoma Cells, Is Mediated by p53-p21 Stabilization and Modulated by Ras/Raf/MEK/ERK Signaling Pathway
Here we first demonstrate that asperolide A, a very recently reported marine-derived tetranorditerpenoid, leads to the inhibition of NCI-H460 lung carcinoma cell proliferation by G2/M arrest with the activation of the Ras/Raf/MEK/ERK signaling and p53-dependent p21 pathway. Treatment with 35 μM aspe...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640382/ https://www.ncbi.nlm.nih.gov/pubmed/23434831 http://dx.doi.org/10.3390/md11020316 |
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author | Lv, Cuiting Sun, Wenxia Sun, Haofen Wei, Shanjian Chen, Ruohua Wang, Bingui Huang, Caiguo |
author_facet | Lv, Cuiting Sun, Wenxia Sun, Haofen Wei, Shanjian Chen, Ruohua Wang, Bingui Huang, Caiguo |
author_sort | Lv, Cuiting |
collection | PubMed |
description | Here we first demonstrate that asperolide A, a very recently reported marine-derived tetranorditerpenoid, leads to the inhibition of NCI-H460 lung carcinoma cell proliferation by G2/M arrest with the activation of the Ras/Raf/MEK/ERK signaling and p53-dependent p21 pathway. Treatment with 35 μM asperolide A (2 × IC(50)) resulted in a significant increase in the proportion of G2/M phase cells, about a 2.9-fold increase during 48 h. Immunoblot assays demonstrated time-dependent inhibition of G2/M regulatory proteins. Moreover, asperolide A significantly activated MAP kinases (ERK1/2, JNK and p38 MAP kinase) by phosphorylation, and only the inhibition of ERK activation by PD98059 reversed downregulation of G2/M regulatory proteins CDC2, and suppressed upregulation of p21 and p-p53 levels. Transfection of cells with dominant-negative Ras (RasN17) mutant genes up-regulated asperolide A-induced the decrease of cyclin B1 and CDC2, suppressed Raf, ERK activity and p53-p21 expression, and at last, abolished G2/M arrest. This study indicates that asperolide A-induced G2/M arrest in human NCI-H460 lung carcinoma cells relys on the participation of the Ras/Raf/MEK/ERK signaling pathway in p53-p21 stabilization. An in vivo study with asperolide A illustrated a marked inhibition of tumor growth, and little toxcity compared to Cisplatin therapy. Overall, these findings provide potential effectiveness and a theoretical basis for the therapeutic use of asperolide A in the treatment of malignancies. |
format | Online Article Text |
id | pubmed-3640382 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-36403822013-05-02 Asperolide A, a Marine-Derived Tetranorditerpenoid, Induces G2/M Arrest in Human NCI-H460 Lung Carcinoma Cells, Is Mediated by p53-p21 Stabilization and Modulated by Ras/Raf/MEK/ERK Signaling Pathway Lv, Cuiting Sun, Wenxia Sun, Haofen Wei, Shanjian Chen, Ruohua Wang, Bingui Huang, Caiguo Mar Drugs Article Here we first demonstrate that asperolide A, a very recently reported marine-derived tetranorditerpenoid, leads to the inhibition of NCI-H460 lung carcinoma cell proliferation by G2/M arrest with the activation of the Ras/Raf/MEK/ERK signaling and p53-dependent p21 pathway. Treatment with 35 μM asperolide A (2 × IC(50)) resulted in a significant increase in the proportion of G2/M phase cells, about a 2.9-fold increase during 48 h. Immunoblot assays demonstrated time-dependent inhibition of G2/M regulatory proteins. Moreover, asperolide A significantly activated MAP kinases (ERK1/2, JNK and p38 MAP kinase) by phosphorylation, and only the inhibition of ERK activation by PD98059 reversed downregulation of G2/M regulatory proteins CDC2, and suppressed upregulation of p21 and p-p53 levels. Transfection of cells with dominant-negative Ras (RasN17) mutant genes up-regulated asperolide A-induced the decrease of cyclin B1 and CDC2, suppressed Raf, ERK activity and p53-p21 expression, and at last, abolished G2/M arrest. This study indicates that asperolide A-induced G2/M arrest in human NCI-H460 lung carcinoma cells relys on the participation of the Ras/Raf/MEK/ERK signaling pathway in p53-p21 stabilization. An in vivo study with asperolide A illustrated a marked inhibition of tumor growth, and little toxcity compared to Cisplatin therapy. Overall, these findings provide potential effectiveness and a theoretical basis for the therapeutic use of asperolide A in the treatment of malignancies. MDPI 2013-01-29 /pmc/articles/PMC3640382/ /pubmed/23434831 http://dx.doi.org/10.3390/md11020316 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Lv, Cuiting Sun, Wenxia Sun, Haofen Wei, Shanjian Chen, Ruohua Wang, Bingui Huang, Caiguo Asperolide A, a Marine-Derived Tetranorditerpenoid, Induces G2/M Arrest in Human NCI-H460 Lung Carcinoma Cells, Is Mediated by p53-p21 Stabilization and Modulated by Ras/Raf/MEK/ERK Signaling Pathway |
title | Asperolide A, a Marine-Derived Tetranorditerpenoid, Induces G2/M Arrest in Human NCI-H460 Lung Carcinoma Cells, Is Mediated by p53-p21 Stabilization and Modulated by Ras/Raf/MEK/ERK Signaling Pathway |
title_full | Asperolide A, a Marine-Derived Tetranorditerpenoid, Induces G2/M Arrest in Human NCI-H460 Lung Carcinoma Cells, Is Mediated by p53-p21 Stabilization and Modulated by Ras/Raf/MEK/ERK Signaling Pathway |
title_fullStr | Asperolide A, a Marine-Derived Tetranorditerpenoid, Induces G2/M Arrest in Human NCI-H460 Lung Carcinoma Cells, Is Mediated by p53-p21 Stabilization and Modulated by Ras/Raf/MEK/ERK Signaling Pathway |
title_full_unstemmed | Asperolide A, a Marine-Derived Tetranorditerpenoid, Induces G2/M Arrest in Human NCI-H460 Lung Carcinoma Cells, Is Mediated by p53-p21 Stabilization and Modulated by Ras/Raf/MEK/ERK Signaling Pathway |
title_short | Asperolide A, a Marine-Derived Tetranorditerpenoid, Induces G2/M Arrest in Human NCI-H460 Lung Carcinoma Cells, Is Mediated by p53-p21 Stabilization and Modulated by Ras/Raf/MEK/ERK Signaling Pathway |
title_sort | asperolide a, a marine-derived tetranorditerpenoid, induces g2/m arrest in human nci-h460 lung carcinoma cells, is mediated by p53-p21 stabilization and modulated by ras/raf/mek/erk signaling pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640382/ https://www.ncbi.nlm.nih.gov/pubmed/23434831 http://dx.doi.org/10.3390/md11020316 |
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