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J. Biol. Chem., Vol. 278, Issue 44, 43586-43594, October 31, 2003

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p21-dependent Inhibition of Colon Cancer Cell Growth by Mevastatin Is Independent of Inhibition of G₁ Cyclin-dependent Kinases^*

Chinweike Ukomadu and Anindya Dutta¶

From the Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908 and the Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Mevastatin arrested HCT116 colon cancer cells at the G₁/S transition and increased cellular levels of p21^CIP1/WAF1. p21-deficient colon cancer cells continued to proliferate in the presence of mevastatin. Although p21 was necessary for the G₁/S block, the G₁ cyclin-dependent kinases (Cdks) cyclin E-Cdk2 and cyclin D-Cdk4 remained active. Despite the activity of the G₁ Cdks the retinoblastoma protein was hypophosphorylated due to unknown mechanisms that were dependent on the p21 protein. The resulting decrease in cyclin A mRNA and protein led to a decrease in the activity of cyclin A-Cdk2. Therefore, although p21 was required for the G₁/S arrest of HCT116 colon cancer cells by mevastatin, its mode of action was more complicated than the simple formation of a physical complex with cyclin-Cdk2. This mechanism of inhibition is different from that seen in prostate cancer cells (Ukomadu, C., and Dutta, A. (2003) J. Biol. Chem. 278, 4840–4846) where the activating phosphorylation of cyclin E-Cdk2 is suppressed and p21 is not required, suggesting the existence of cell line-specific differences in the mechanism by which statins arrest the cell cycle.

Received for publication, July 5, 2003 , and in revised form, August 11, 2003.

^* This work was supported by National Institutes of Health Grant RO1 CA89406 (to A. D.) and by a Howard Hughes Medical Institute postdoctoral fellowship and a Foundation of Digestive Health and Nutrition research scholar's award (to C. U.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 434-924-1227; Fax: 434-924-5069; E-mail: ad8q{at}virginia.edu.

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