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A Vitamin D₃ Analog Induces a G1-Phase Arrest in CaCo-2 Cells by Inhibiting Cdk2 and Cdk6: Roles of Cyclin E, p21^Waf1, and p27^Kip11

Gastroenterology Section, Department of Medicine, The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: T. A. Brasitus, Gastroenterology Section, Department of Medicine, The University of Chicago, MC4076, 5841 South Maryland Avenue, Chicago Illinois 60637. E-mail: tbrasitu{at}medicine.bsd.uchicago.edu

Previous studies by our laboratory have shown that a noncalcemic fluorinated analog of 1,25-dihydroxyvitamin D₃, 1,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholcalciferol (F₆-D₃), significantly reduced the frequency of colonic adenomas and completely abolished the development of colonic adenocarcinomas in rats treated with azoxymethane. The mechanisms involved in this analog’s chemopreventive actions, however, remain unclear. In the present study, we now show that although both 1,25-dihydroxyvitamin D₃ and F₆-D₃ inhibited the proliferation of CaCo-2 cells, a human colonic adenocarcinoma cell line, by increasing their doubling times, only F₆-D₃ caused an arrest of these cells in the G1 phase of their cell cycle. This arrest was accompanied by an increase in the expression of the cyclin-dependent kinase (cdk) inhibitor proteins, p21^Waf1 and p27^Kip1, which served to decrease the activity of cyclin-dependent kinase 2 and cyclin-dependent kinase 6, whereas the expression and phosphorylation of pRB were unchanged. In contrast to the increased expression of these cdk inhibitors, the expression of cyclin E was decreased, which further inhibited the activity of cyclin-dependent kinase 2. Collectively, the inhibition of these cyclin-dependent kinases served to arrest the CaCo-2 cells, independent of changes in pRB. Furthermore, antibody neutralization studies suggest that transforming growth factor-ß may mediate the coassociations between cdk2 and p27^Kip1 and cyclin E induced by F₆-D₃. These data indicate that cell cycle arrest may, at least in part, underlie the chemopreventive actions of F₆-D₃ observed in the azoxymethane model of colon cancer. Furthermore, if the antiproliferative action observed in CaCo-2 cells also occurs in human colonic epithelium, F₆-D₃ may have chemopreventive potential against human colon cancer, as well.

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