Gallic acid induces G2/M phase cell cycle arrest via regulating 14-3-3β release from Cdc25C and Chk2 activation in human bladder transitional carcinoma cells

• Published in: Molecular nutrition & food research 2010-12, Vol.54 (12), p.1781-1790
• Main Authors: Ou, Ting-Tsz, Wang, Chau-Jong, Lee, Yung-Shu, Wu, Cheng-Hsun, Lee, Huei-Jane
• Format: Article
• Language: English
• Subjects: 14-3-3 Proteins - metabolism; Analysis of Variance; Biological and medical sciences; cdc25 Phosphatases - metabolism; Cell Cycle; Cell Division; Cell Line, Tumor; Checkpoint Kinase 2; Cyclin B1 - metabolism; Cyclin-Dependent Kinases - metabolism; Food industries; Fundamental and applied biological sciences. Psychology; G2 Phase; G2/M phase; Gallic acid; Gallic Acid - pharmacology; Human bladder transitional carcinoma; Humans; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Urinary Bladder Neoplasms - metabolism
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201000096

Scope: Cell cycle regulation is a critical issue in cancer treatment. Previously, gallic acid (GA) has been reported to possess anticancer ability. Here, we have evaluated the molecular mechanism of GA on cell cycle modulation in a human bladder transitional carcinoma cell line (TSGH-8301 cell). Methods and results: Using flow cytometer analysis, exposure of the cells to 40 μM GA resulted in a statistically significant increase in G2/M phase cells, which was accompanied by a decrease in G0/G1 phase cells. GA-treated cells resulted in significant growth inhibition in a dose-dependent manner accompanied by a decrease in cyclin-dependent kinases (Cdk1), Cyclin B1, and Cdc25C, but significant increases in p-cdc2 (Tyr-15) and Cip1/p21 by western blotting. Additional mechanistic studies showed that GA induces phosphorylation of Cdc25C at Ser-216. This mechanism leads to its translocation from the nucleus to the cytoplasm resulting in an increased binding with 14-3-3β. When treated with GA, phosphorylated Cdc25C can be activated by ataxia telangiectasia-mutated checkpoint kinase 2 (Chk2). This might be a DNA damage response as indicated by Ser-139 phosphorylation of histine H2A.X. Furthermore, treatment of the cells with a Chk2 inhibitor significantly attenuated GA-induced G2/M phase arrest. Conclusion: These results indicate that GA can induce cell cycle arrest at G2/M phase via Chk2-mediated phosphorylation of Cdc25C in a bladder transitional carcinoma cell line.