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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies reported worldwide, and accounts for 4.6% of all neoplasias
We further explored the mechanism by which Longikaurin A (LK-A) may inhibit malignant proliferation, such as by downregulating Skp[2] and inducing cell cycle arrest, and by causing apoptosis activated by reactive oxygen species (ROS)/ c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway induction
To further examine the mechanism by which LK-A may inhibit proliferation of SMMC-7721 and HepG2 cells, we studied the effects of LK-A on cell cycle arrest
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies reported worldwide, and accounts for 4.6% of all neoplasias. S phase kinase-associated protein 2 (Skp2), is the F-box component of an E3 ubiquitin ligase, and may interact with several proteins, including p21Cip[1,5,6,7] p27Kip[1,8,9,10] p57Kip[2] and p130.11,12 Skp[2] function likely leads to degradation of tumor suppressor proteins, such as Cdk inhibitors p21 and p27, inducing formation of the Cdk complex and thereby accelerating cell cycle progression
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