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Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27Kip1 in the cyclin E–cdk2 complexes

Abstract

Numerous studies have demonstrated the anticancer activity of the tomato carotenoid, lycopene. However, the molecular mechanism of this action remains unknown. Lycopene inhibition of human breast and endometrial cancer cell growth is associated with inhibition of cell cycle progression at the G1 phase. In this study we determined the lycopene-mediated changes in the cell cycle machinery. Cells synchronized in the G1 phase by serum deprivation were treated with lycopene or vehicle and restimulated with 5% serum. Lycopene treatment decreased serum-induced phosphorylation of the retinoblastoma protein and related pocket proteins. This effect was associated with reduced 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 p21Cip1/Waf1 abundance was reduced while p27Kip1 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 cyclin 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 cyclin E–cdk2, thus leading to inhibition of G1 CDK activities.

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Acknowledgements

We thank Prof Robert L Sutherland, Dr Elizabeth A Musgrove, Alex Swarbrick and Angela Lei (Garvan Institute of Medical Research, Sydney) for the many helpful discussions and the technical support. We thank Dr Zohar Nir, LycoRed Natural Products Industries, Beer Sheva, Israel for donating purified lycopene. The studies were supported in part by the Israel Science Foundation founded by the Israel Academy of Science and Humanities; by LycoRed Natural Products Industries, Beer-Sheva, Israel; and by the S Daniel Abraham International Center for Health and Nutrition, Ben-Gurion University of the Negev.

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Nahum, A., Hirsch, K., Danilenko, M. et al. Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27Kip1 in the cyclin E–cdk2 complexes. Oncogene 20, 3428–3436 (2001). https://doi.org/10.1038/sj.onc.1204452

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Keywords

  • lycopene
  • breast cancer
  • endometrial cancer
  • cell cycle
  • cyclin D1
  • retinoblastoma
  • p27kip1

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