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...
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| Format: | Article |
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MDPI AG
2013-01-01
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| Series: | Marine Drugs |
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| Online Access: | http://www.mdpi.com/1660-3397/11/2/316 |
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| author | Caiguo Huang Bingui Wang Ruohua Chen Shanjian Wei Haofen Sun Cuiting Lv Wenxia Sun |
| author_facet | Caiguo Huang Bingui Wang Ruohua Chen Shanjian Wei Haofen Sun Cuiting Lv Wenxia Sun |
| author_sort | Caiguo Huang |
| collection | DOAJ |
| 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 × IC50) 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. |
| first_indexed | 2024-04-14T05:28:16Z |
| format | Article |
| id | doaj.art-79b4d137025142208acbe7b7bd4e1ee5 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-14T05:28:16Z |
| publishDate | 2013-01-01 |
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| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-79b4d137025142208acbe7b7bd4e1ee52022-12-22T02:09:55ZengMDPI AGMarine Drugs1660-33972013-01-0111231633110.3390/md11020316Asperolide 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 PathwayCaiguo HuangBingui WangRuohua ChenShanjian WeiHaofen SunCuiting LvWenxia SunHere 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 × IC50) 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.http://www.mdpi.com/1660-3397/11/2/316asperolide AG2/M arrestp53-p21Ras/Raf/MEK/ERK signaling pathway |
| spellingShingle | Caiguo Huang Bingui Wang Ruohua Chen Shanjian Wei Haofen Sun Cuiting Lv Wenxia Sun 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 Marine Drugs asperolide A G2/M arrest p53-p21 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 | asperolide A G2/M arrest p53-p21 Ras/Raf/MEK/ERK signaling pathway |
| url | http://www.mdpi.com/1660-3397/11/2/316 |
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