Longikaurin A, a natural ent-kaurane, induces G2/M phase arrest via downregulation of Skp2 and apoptosis induction through ROS/JNK/c-Jun pathway in hepatocellular carcinoma cells
Liao, Y-J1; Bai, H-Y1,2; Li, Z-H2; Zou, J.3; Chen, J-W1; Zheng, F.4; Zhang, J-X1; Mai, S-J1; Zeng, M-S1; Sun, H-D3; Pu, J-X3; Xie, D.1
2014-03-01
发表期刊CELL DEATH & DISEASE
ISSN2041-4889 ; 2041-4889
卷号5页码:e1137
摘要Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and is also highly resistant to conventional chemotherapy treatments. In this study, we report that Longikaurin A (LK-A), an ent-kaurane diterpenoid isolated from the plant Isodon ternifolius, induced cell cycle arrest and apoptosis in human HCC cell lines. LK-A also suppressed tumor growth in SMMC-7721 xenograft models, without inducing any notable major organ-related toxicity. LK-A treatment led to reduced expression of the proto-oncogene S phase kinase-associated protein 2 (Skp2) in SMMC-7721 cells. Lower Skp2 levels correlated with increased expression of p21 and p-cdc2 (Try15), and a corresponding decrease in protein levels of Cyclin B1 and cdc2. Overexpression of Skp2 significantly inhibited LK-A-induced cell cycle arrest in SMMC-7721 cells, suggesting that LK-A may target Skp2 to arrest cells at the G2/M phase. LK-A also induced reactive oxygen species (ROS) production and apoptosis in SMMC-7721 cells. LK-A induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase and P38 MAP kinase. Treatment with, the JNK inhibitor SP600125 prevented LK-A-induced apoptosis in SMMC-7721 cells. Moreover, the antioxidant N-acetylcysteine prevented phosphorylation of both JNK and c-Jun. Taken together, these data indicate that LK-A induces cell cycle arrest and apoptosis in cancer cells by dampening Skp2 expression, and thereby activating the ROS/JNK/c-Jun signaling pathways. LK-A is therefore a potential lead compound for development of antitumor drugs targeting HCC.
关键词Longikaurin a Hepatocellular Carcinoma Cell Cycle Arrest Apoptosis Skp2
资助信息National Natural Science Foundation of China [81225018, 81172340, 81172939]; West Light of Foundation of Chinese Academy of Sciences; National Natural Science Foundation of China [81225018, 81172340, 81172939]; West Light of Foundation of Chinese Academy of Sciences
学科领域Cell Biology ; Cell Biology
DOI10.1038/cddis.2014.66
收录类别SCI
语种英语
WOS研究方向Cell Biology
WOS类目Cell Biology
WOS记录号WOS:000333754100041
引用统计
被引频次:34[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/18045
专题植物化学与西部植物资源持续利用国家重点实验室
作者单位1.Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Guangzhou 510060, Guangdong, Peoples R China
2.Sun Yat Sen Univ, Zhongshan Sch Med, Dept Forens Med, Guangzhou 510060, Guangdong, Peoples R China
3.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming, Peoples R China
4.Sun Yat Sen Mem Hosp, Med Res Ctr, Guangzhou, Guangdong, Peoples R China
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GB/T 7714
Liao, Y-J,Bai, H-Y,Li, Z-H,et al. Longikaurin A, a natural ent-kaurane, induces G2/M phase arrest via downregulation of Skp2 and apoptosis induction through ROS/JNK/c-Jun pathway in hepatocellular carcinoma cells[J]. CELL DEATH & DISEASE,2014,5:e1137, e1137.
APA Liao, Y-J.,Bai, H-Y.,Li, Z-H.,Zou, J..,Chen, J-W.,...&Xie, D..(2014).Longikaurin A, a natural ent-kaurane, induces G2/M phase arrest via downregulation of Skp2 and apoptosis induction through ROS/JNK/c-Jun pathway in hepatocellular carcinoma cells.CELL DEATH & DISEASE,5,e1137.
MLA Liao, Y-J,et al."Longikaurin A, a natural ent-kaurane, induces G2/M phase arrest via downregulation of Skp2 and apoptosis induction through ROS/JNK/c-Jun pathway in hepatocellular carcinoma cells".CELL DEATH & DISEASE 5(2014):e1137.
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