Lycopene and other carotenoids inhibit estrogenic activity of 17β-estradiol and genistein in cancer cells
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Epidemiological evidence suggests that carotenoids prevent several types of cancer, including mammary and endometrial cancers. On the other hand, such studies have also shown that estrogens are the most important risk factors for these cancer types. Genistein, the phytoestrogen mainly found in soy, also shows significant estrogenic activity when tested at concentrations found in human blood. The aim of this study was to determine whether carotenoids inhibit signaling of steroidal estrogen and phytoestrogen which could explain their cancer preventive activity. Similar to the known effect of 17β-estradiol (E2), treatment of breast (T47D and MCF-7) and endometrial (ECC-1) cancer cells with phytoestrogens induced cell proliferation, cell-cycle progression and transactivation of the estrogen response element (ERE). However, each of the tested carotenoids (lycopene, phytoene, phytofluene, and β-carotene) inhibited cancer cell proliferation induced by either E2 or genistein. The inhibition of cell growth by lycopene was accompanied by slow down of cell-cycle progression from G1 to S phase. Moreover, the carotenoids inhibited estrogen-induced transactivation of ERE that was mediated by both estrogen receptors (ERs) ERα and ERβ. The possibility that this inhibition results from competition of carotenoid-activated transcription systems on a limited pool of shared coactivators with the ERE transcription system was tested. Although cotransfection of breast and endometrial cancer cells with four different coactivators (SRC-1, SRC-2, SRC-3, and DRIP) strongly stimulated ERE reporter gene activity, it did not oppose the inhibitory effect of carotenoids. These results suggest that dietary carotenoids inhibit estrogen signaling of both 17β-estradiol and genistein, and attenuate their deleterious effect in hormone-dependent malignancies.
KeywordsCarotenoids Cell cycle Coactivators Estrogen receptor Genistein Lycopene Phytoene Phytofluene Soy isoflavones
We thank Dr. Zohar Nir, LycoRed Natural Products Industries, Beer Sheva, Israel, for donating purified lycopene, phytoene and phytofluene. We thank Dr. M. Parker (Imperial Cancer Research Fund, London, UK), Dr. P. Chambon (Institute of Genetic and Cellular and Molecular Biology, Strasburg, France), Dr. R.M. Evans (Salk Institute, La Jolla, CA, USA), and Dr. L.P. Freedman (Cornell University, NY, USA) for donating the plasmids that were used in this study. 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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