Journal Article

Tangeretin induces cell-cycle G<sub>1</sub> arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells

Min-Hsiung Pan, Wei-Jen Chen, Shoei-Yn Lin-Shiau, Chi-Tang Ho and Jen-Kun Lin

in Carcinogenesis

Volume 23, issue 10, pages 1677-1684
Published in print October 2002 | ISSN: 0143-3334
Published online October 2002 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/23.10.1677
Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells

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Tangeretin (5,6,7,8,4’-pentamethoxyflavone) is concentrated in the peel of citrus fruits. DNA flow cytometric analysis indicated that tangeretin blocked cell cycle progression at G1 phase in colorectal carcinoma COLO 205 cells. Over a 24 h exposure to tangeretin, the degree of phosphorylation of Rb was decreased after 12 h and G1 arrest developed. The protein expression of cyclins A, D1, and E reduced slightly under the same conditions. Immunocomplex kinase experiments showed that tangeretin inhibited the activities of cyclin-dependent kinases 2 (Cdk2) and 4 (Cdk4) in a dose-dependent manner in the cell-free system. As the cells were exposed to tangeretin (50 μM) over 48 h a gradual loss of both Cdk2 and 4 kinase activities occurred. Tangeretin also increased the content of the Cdk inhibitor p21 protein and this effect correlated with the elevation in p53 levels. In addition, tangeretin also increased the level of the Cdk inhibitor p27 protein within 18 h. These results suggest that tangeretin either exerts its growth-inhibitory effects through modulation of the activities of several key G1 regulatory proteins, such as Cdk2 and Cdk4, or mediates the increase of Cdk inhibitors p21 and p27.

Journal Article.  5782 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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