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Carcinogenesis Advance Access originally published online on September 28, 2006
Carcinogenesis 2007 28(3):632-638; doi:10.1093/carcin/bgl168
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Gambogic acid-induced G2/M phase cell-cycle arrest via disturbing CDK7-mediated phosphorylation of CDC2/p34 in human gastric carcinoma BGC-823 cells

Jun Yu{dagger}, Qing-Long Guo{dagger}, Qi-Dong You1,*, Li Zhao, Hong-Yan Gu, Yong Yang, Hai-wei Zhang, Zi Tan2 and Xiaotang Wang2,*

Department of Physiology, China Pharmaceutical University Nanjing 210009, People's Republic of China
1 Department of Medicinal Chemistry, China Pharmaceutical University Nanjing 210009, People's Republic of China
2 Department of Chemistry and Biochemistry, Florida International University Miami, FL 33199, USA

*To whom correspondence should be addressed. Q.Y., Tel: +86 25 83271351; Fax: +86 25 83271055; Email: anticancer_drug{at}yahoo.com.cn;X.W., Tel: +1 305 348 7544; Fax: +1 305 348 3772; Email: wangx{at}fiu.edu

Molecular mechanisms of cell-cycle arrest caused by gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburryi tree, have been investigated using BGC-823 human gastric carcinoma cells as a model. Based on our 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazoliumbromide (MTT) assay and flow cytometric analysis, treatment of BGC-823 cells with growth suppressive concentrations of GA caused an irreversible arrest in the G2/M phase of the cell cycle. Western blot analysis demonstrated that GA-induced cell-cycle arrest in BGC-823 cells was associated with a significant decrease in CDC2/p34 synthesis, which led to the accumulation of phosphorylated-Tyr15 (inactive) form of CDC2/p34. Real-time PCR, western blot and kinase activity assays revealed that GA-induced reduction of CDC2/p34 expression was mediated through the inhibition of cyclin-dependent kinase (CDK)-activating kinase (CDK7/cyclin H) activity. In addition, GA-treated cells were shown to have a low level of CDK7 kinase-phosphorylated-Thr161 CDC2/p34 (active). Taken together, our results suggested that the inhibited proliferation of GA-treated BGC-823 cells was associated with the decreased production of CDK7 mRNA and protein, which in turn, resulted in the reduction of CDK7 kinase activity. The reduced CDK7 kinase activity is responsible for the inactivation of CDC2/p34 kinase and the irreversible G2/M phase cell-cycle arrest of human gastric carcinoma BGC-823 cells.

Abbreviations: GA, gambogic acid; CAK, CDK-activating kinase; CDK, cyclin-dependent kinase; MPF, mitosis-promoting factor; PBS, physiologically buffered saline

{dagger}These authors contributed equally to this work.

Received December 29, 2005; revised August 2, 2006; accepted August 13, 2006.


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