QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tibaduiza, E. C. Articles by Krinsky, N. I. Search for Related Content PubMed PubMed Citation Articles by Tibaduiza, E. C. Articles by Krinsky, N. I.

---

Nutrition and Cancer

Excentric Cleavage Products of ß-Carotene Inhibit Estrogen Receptor Positive and Negative Breast Tumor Cell Growth In Vitro and Inhibit Activator Protein-1-Mediated Transcriptional Activation¹

Elmi C. Tibaduiza^*, James C. Fleet, Robert M. Russell^** and Norman I. Krinsky^**,2

^* Molecular Pharmacology Research Center at the New England Medical Center, Boston, MA 02111; Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47906; ^** Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; and the Department of Biochemistry, School of Medicine, Tufts University, Boston, MA 02111

²To whom correspondence should be addressed. E-mail: norman.krinsky{at}tufts.edu

Both retinoids and carotenoids are potentially useful chemopreventive agents. In this study we tested the effect of synthetic excentric cleavage products of ß-carotene on the growth of the MCF-7, Hs578T and MDA-MB-231 human breast cancer cells. The apo-ß-carotenoic acids (ß-apo-CA) ß-apo-14'-, ß-apo-12'-, ß-apo-10'- and ß-apo-8'-CA are structurally similar to all-trans-retinoic acid (atRA) but have different side chain lengths. Nine days of treatment with atRA inhibited MCF-7 and Hs578T cell proliferation in a dose-dependent manner. ß-apo-14'-CA and ß-apo-12'-CA significantly inhibited MCF-7 growth, whereas only ß-apo-14'-CA inhibited Hs578T growth. None of these treatments inhibited the growth of MDA-MB-231 cells. Potential mechanisms of growth inhibition, i.e., regulation of the cell cycle control proteins E2F1 and retinoblastoma protein (RB), and effect on activator protein-1 (AP-1)-mediated gene regulation were examined. ß-apo-14'-CA and atRA inhibited the expression of E2F1 protein in MCF-7 and Hs578T cells. ß-apo-14'-CA, ß-apo-12'-CA and atRA down-regulated RB protein expression in MCF-7 but not in Hs578T cells. The effect of phorbol ester-induced transcriptional activation of a collagenase promoter-reporter gene construct was strongly inhibited by 1 µmol/L ß-apo-14'-CA, atRA (MCF-7, Hs578T) or ß-apo-12'-CA (MCF-7). These effects were due neither to cellular conversion of ß-apo-CA to atRA nor to high affinity binding to the retinoid acid receptors. Thus, ß-apo-CAs were effective inhibitors of breast tumor cell proliferation, possibly mediated through down-regulation of cell cycle regulatory proteins and/or inhibition of AP-1 transcriptional activity. The ability of ß-apo-CA to regulate breast tumor cell growth independently of conversion to atRA suggests that these compounds may have fewer side effects than retinoids and, therefore, have a potential chemotherapeutic value that deserves further examination.

KEY WORDS: • ß-carotene • excentric cleavage • breast tumor cells • activator protein-1 • retinoblastoma protein • E2F1

This article has been cited by other articles:

				K.-Q. Hu, C. Liu, H. Ernst, N. I. Krinsky, R. M. Russell, and X.-D. Wang The Biochemical Characterization of Ferret Carotene-9', 10'-Monooxygenase Catalyzing Cleavage of Carotenoids in Vitro and in Vivo J. Biol. Chem., July 14, 2006; 281(28): 19327 - 19338. [Abstract] [Full Text] [PDF]

				M. Gajic, S. Zaripheh, F. Sun, and J. W. Erdman Jr. Apo-8'-Lycopenal and Apo-12'-Lycopenal Are Metabolic Products of Lycopene in Rat Liver J. Nutr., June 1, 2006; 136(6): 1552 - 1557. [Abstract] [Full Text] [PDF]

				C. Rousseau, J. N. Nichol, F. Pettersson, M.-C. Couture, and W. H. Miller Jr. ER{beta} Sensitizes Breast Cancer Cells to Retinoic Acid: Evidence of Transcriptional Crosstalk Mol. Cancer Res., September 1, 2004; 2(9): 523 - 531. [Abstract] [Full Text] [PDF]

				P. Prakash, C. Liu, K.-Q. Hu, N. I. Krinsky, R. M. Russell, and X.-D. Wang {beta}-Carotene and {beta}-Apo-14'-Carotenoic Acid Prevent the Reduction of Retinoic Acid Receptor {beta} in Benzo[a]pyrene-Treated Normal Human Bronchial Epithelial Cells J. Nutr., March 1, 2004; 134(3): 667 - 673. [Abstract] [Full Text] [PDF]

				M. S. Irwig, A. El-Sohemy, A. Baylin, N. Rifai, and H. Campos Frequent Intake of Tropical Fruits That Are Rich in {beta}-Cryptoxanthin Is Associated with Higher Plasma {beta}-Cryptoxanthin Concentrations in Costa Rican Adolescents J. Nutr., October 1, 2002; 132(10): 3161 - 3167. [Abstract] [Full Text] [PDF]