Resveratrol-induced G2 arrest through the inhibition of CDK7 and p34CDC2 kinases in colon carcinoma HT29 cells.
Resveratrol (3,5,4'-trihydroxystilbene), a phytoalexin found in grapes and other food products, has been shown to have cancer chemopreventive activity. However, the mechanism of the anti-carcinogenic activity is not well understood. Here, we offer a possible explanation of its anti-tumor effect. Based on flow cytometric analysis, resveratrol inhibited the proliferation of HT29 colon cancer cells and resulted in their accumulation in the G(2) phase of the cell cycle. Western blot analysis and kinase assays demonstrated that the perturbation of G(2) phase progression by resveratrol was accompanied by the inactivation of p34(CDC2) protein kinase, and an increase in the tyrosine phosphorylated (inactive) form of p34(CDC2). Kinase assays revealed that the reduction of p34(CDC2) activity by resveratrol was mediated through the inhibition of CDK7 kinase activity, while CDC25A phosphatase activity was not affected. In addition, resveratrol-treated cells were shown to have a low level of CDK7 kinase-Thr(161)-phosphorylated p34(CDC2). These results demonstrated that resveratrol induced cell cycle arrest at the G(2) phase through the inhibition of CDK7 kinase activity, suggesting that its anti-tumor activity might occur through the disruption of cell division at the G(2)/M phase.
Liang
Yu-Chih
YC
Institute of Biochemistry & Molecular Biology, College of Medicine, National Taiwan University, No. 1, Section 1 Jen-ai Road, Taipei, Taiwan
Tsai
Shu-Huei
SH
Chen
Linda
L
Lin-Shiau
Shoei-Yn
SY
Lin
Jen-Kun
JK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016195:G2 Phase / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000378:metabolism; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D000970:Antineoplastic Agents; D013267:Stilbenes; D018844:Cyclin-Dependent Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D000077185:Resveratrol; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human