Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention ofp27(Kip1) in the cyclin E-cdk2 complexes

Numerous studies have demonstrated the anticancer activity of the tomato ca rotenoid, lycopene. However, the molecular mechanism of this action remains unknown. Lycopene inhibition of human breast and endometrial cancer cell g rowth is associated with inhibition of cell cycle progression at the G(1) p hase. In this study we determined the lycopene-mediated changes in the cell cycle machinery. Cells synchronized in the G1 phase by serum deprivation w ere treated with lycopene or vehicle and restimulated with 5% serum. Lycope ne treatment decreased serum-induced phosphorylation of the retinoblastoma protein and related pocket proteins. This effect was associated with reduce d cyclin-dependent kinase (cdk4 and cdk2) activities with no alterations in CDK protein levels. Lycopene caused a decrease in cyclin D1 and D3 levels whereas cyclin E levels did not change. The CDK inhibitor p21(Cip1/Waf1) ab undance was reduced while p27(Kip1) levels were unaltered in comparison to control cells. Serum stimulation of control cells resulted in reduction in the p27 content in the cyclin E-cdk2 complex and its accumulation in the cy clin D1-cdk4 complex. This change in distribution was largely prevented by lycopene treatment. These results suggest that lycopene inhibits cell cycle progression via reduction of the cyclin D level and retention of p27 in cy clin E-cdk2, thus leading to inhibition of G(1) CDK activities.