1. 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.
- Author
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Liao YJ, Bai HY, Li ZH, Zou J, Chen JW, Zheng F, Zhang JX, Mai SJ, Zeng MS, Sun HD, Pu JX, and Xie D
- Subjects
- Animals, CDC2 Protein Kinase, Carcinoma, Hepatocellular enzymology, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Cyclin B metabolism, Cyclin B1 metabolism, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cyclin-Dependent Kinases, Dose-Response Relationship, Drug, Down-Regulation, Hep G2 Cells, Humans, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, Liver Neoplasms enzymology, Liver Neoplasms genetics, Liver Neoplasms pathology, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Phosphorylation, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Mas, S-Phase Kinase-Associated Proteins genetics, Time Factors, Transfection, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents, Phytogenic pharmacology, Apoptosis drug effects, Carcinoma, Hepatocellular drug therapy, Diterpenes, Kaurane pharmacology, G2 Phase Cell Cycle Checkpoints drug effects, JNK Mitogen-Activated Protein Kinases metabolism, Liver Neoplasms drug therapy, Proto-Oncogene Proteins c-jun metabolism, Reactive Oxygen Species metabolism, S-Phase Kinase-Associated Proteins metabolism, Signal Transduction drug effects
- Abstract
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.
- Published
- 2014
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