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题名: 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
作者: 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
刊名: CELL DEATH & DISEASE
关键词: Longikaurin A ; hepatocellular carcinoma ; cell cycle arrest ; apoptosis ; Skp2
英文摘要: 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.
出版日期: 2014-03-01
卷号: 5, 页码:e1137
语种: 英语
收录类别: SCI
学科分类: Cell Biology ; Cell Biology
ISSN号: 2041-4889 ; 2041-4889
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.kib.ac.cn/handle/151853/18045
Appears in Collections:植物化学与西部植物资源持续利用国家重点实验室_期刊论文

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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

Recommended Citation:
Liao,Y-J;Bai,H-Y;Li,Z-H;Zou,J.;Chen,J-W;Zheng,F.;Zhang,J-X;Mai,S-J;Zeng,M-S;Sun,H-D;Pu,J-X;Xie,D..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,2014,5():e1137
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