Institutional Repository of Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences
| 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, Cuiting1; Sun, Wenxia1; Sun, Haofen2; Wei, Shanjian1; Chen, Ruohua3; Wang, Bingui2 ; Huang, Caiguo1; Chen, RH
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| 2013-02-01 | |
| 发表期刊 | MARINE DRUGS
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| ISSN | 1660-3397 |
| 卷号 | 11期号:2页码:316-331 |
| 文章类型 | Article |
| 摘要 | 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 mu M asperolide A (2 x 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.; 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 mu M asperolide A (2 x 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. |
| 关键词 | Asperolide a G2/m Arrest P53-p21 Ras/raf/mek/erk Signaling Pathway |
| 学科领域 | Pharmacology & Pharmacy |
| DOI | 10.3390/md11020316 |
| URL | 查看原文 |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS研究方向 | Pharmacology & Pharmacy |
| WOS类目 | Chemistry, Medicinal |
| WOS记录号 | WOS:000315396800003 |
| WOS关键词 | DNA-DAMAGE ; CYCLE ARREST ; RISK-FACTORS ; P53 GENE ; APOPTOSIS ; KINASE ; CANCER ; ERK ; ACTIVATION ; MITOGEN |
| WOS标题词 | Science & Technology ; Life Sciences & Biomedicine |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://ir.qdio.ac.cn/handle/337002/16530 |
| 专题 | 实验海洋生物学重点实验室 |
| 通讯作者 | Chen, RH |
| 作者单位 | 1.Second Mil Med Univ, Coll Basic Med, Dept Biochem & Mol Biol, Shanghai 200433, Peoples R China 2.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao 266071, Peoples R China 3.Changhai Hosp, VIP Med Dept, Shanghai 200433, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lv, Cuiting,Sun, Wenxia,Sun, Haofen,et al. 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[J]. MARINE DRUGS,2013,11(2):316-331. |
| APA | Lv, Cuiting.,Sun, Wenxia.,Sun, Haofen.,Wei, Shanjian.,Chen, Ruohua.,...&Chen, RH.(2013).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,11(2),316-331. |
| MLA | Lv, Cuiting,et al."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 11.2(2013):316-331. |
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