Casticin induces growth suppression and cell cycle arrest through activation of FOXO3a in hepatocellular carcinoma.

Abstract

Casticin, a polymethoxyflavone, has been reported to exert anticancer activities. The objectives of this study were to examine the molecular mechanisms by which casticin induces the growth inhibition and cell cycle arrest in human hepatocellular carcinoma (HCC) cells. The HCC cell lines Hep G2 and PLC/PRF/5 were cultured in vitro. The growth inhibitory effects of casticin were evaluated using clonogenic assays. The distribution of phases in the cell cycle was analyzed using flow cytometry (FCM) analysis with propidium iodide (PI) staining. Multiple molecular techniques, such as western blotting and gene transfection, were used to explore the molecular mechanisms of action. Our data demonstrated that casticin significantly inhibited cell viability and colony formation in HCC cells. Furthermore, it induced cell cycle arrest in the G2/M phase. Casticin inhibited phosphorylation of the FOXO3a protein and decreased the expression of FoxM1 and its downstream genes, such as cyclin-dependent kinase (CDK1), cdc25B and cyclin B and increased the expression of p27KIP1. Silencing of FOXO3a expression by small interfering RNA (siRNA) transfection clearly attenuated the inhibitory effects of casticin on FOXM1 expression and cell growth. Our findings provided clear evidence that casticin induces growth suppression and cell cycle arrest through inhibition of FOXO3a phosphorylation causing inactivation of FOXM1 in HCC cells.

• Authors: Lihua He, Xiaohong Yang, Xiaocheng Cao, Fei Liu, Meifang Quan, Jianguo Cao
• Journal: Oncology reports (Oncol Rep) Vol. 29 Issue 1 Pg. 103-8 (Jan 2013) ISSN: 1791-2431 [Electronic] Greece
• PMID: 23064420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin B
• FOXM1 protein, human
• FOXO3 protein, human
• Flavonoids
• Forkhead Box Protein M1
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• RNA, Small Interfering
• Cyclin-Dependent Kinase Inhibitor p27
• casticin
• Proto-Oncogene Proteins c-akt

Topics

• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclin B (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Flavonoids (pharmacology)
• Forkhead Box Protein M1
• Forkhead Box Protein O3
• Forkhead Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (genetics)
• Tumor Cells, Cultured