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Lycopene inhibition of IGF-induced cancer cell growth depends on the level of cyclin D1

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Summary

Background

Insulin-like growth factors (IGFs) play an important role in normal and cancerous cell proliferation. Moreover, in recent studies IGF-I has been implicated as a major cancer risk factor. The tomato carotenoid lycopene and all-trans retinoic acid (atRA) have been shown to inhibit growth factor-induced proliferation of different types of cancer cells. This action is associated with inhibition of cell cycle progression in G0/G1 phase. Cyclin D1 acts as a growth factor sensor in G1 phase and is overexpressed in many breast cancer tumors. We have previously demonstrated that slowdown of serum-stimulated cell cycle progression from G1 to S phase by lycopene correlates with reduction in cyclin D1 levels, suggesting that the expression of this protein is a main target for lycopene’s action.

Aim of the study

To determine whether the reported reduction in cyclin D1 level is the key mechanism for lycopene and atRA inhibitory action on IGF-I-induced cell cycle progression.

Results

Human breast (MCF-7) and endometrial (ECC-1) cancer cells were synchronized in G0/G1 phase by serum deprivation followed by stimulation with IGF-I. Cell treatment with lycopene and atRA inhibited IGF-I-stimulated cell cycle progression from G1 to S phase and decreased retinoblastoma protein (pRb) phosphorylation. These events were associated with a reduction in cyclin D1 and p21CIP1/WAF1 level, but not that of p27KIP1. To test the hypothesis that the decrease in cyclin D1 has a major role in the inhibitory effects of lycopene and atRA, we examined the ability of these two agents to suppress cell cycle progression in MCF-7.7D1.13 cells which are capable of expressing cyclin D1 under the control of the Zn-inducible metallothionein promoter. Our results showed that ectopic expression of cyclin D1 can overcome cell cycle inhibition caused by lycopene and atRA.

Conclusions

Our findings suggest that attenuation of cyclin Dl levels by lycopene and atRA is an important mechanism for the reduction of the mitogenic action of IGF-I.

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Acknowledgments

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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Authors and Affiliations

  1. Dept. of Clinical Biochemistry Faculty of Health Sciences, Ben-Gurion University of the Negev and Soroka Medical Center of Kupat Holim, Beer-Sheva, Israel

    Amit Nahum, Lior Zeller, Michael Danilenko, Joseph Levy & Yoav Sharoni

  2. Cancer Research Program Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, NSW, Australia

    Owen W. J. Prall, Colin K. W. Watts & Robert L. Sutherland

  3. Dept. of Clinical Biochemistry Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva, 84105, Israel

    Joseph Levy

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  1. Amit Nahum
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  2. Lior Zeller
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  4. Owen W. J. Prall
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  7. Joseph Levy
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Correspondence to Joseph Levy.

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Nahum, A., Zeller, L., Danilenko, M. et al. Lycopene inhibition of IGF-induced cancer cell growth depends on the level of cyclin D1. Eur J Nutr 45, 275–282 (2006). https://doi.org/10.1007/s00394-006-0595-x

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  • DOI: https://doi.org/10.1007/s00394-006-0595-x

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