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http://dx.doi.org/10.3746/jkfn.2003.32.3.428

Effect of Carotenoids on the Growth of HT-29 Human Colon Cancer Cells  

Frederick Khachik (Joint Institute for Food Safety & Applied Nutrition, University of Maryland)
Publication Information
Journal of the Korean Society of Food Science and Nutrition / v.32, no.3, 2003 , pp. 428-436 More about this Journal
Abstract
Epidemiological studies have observed a negative association between increased consumption of green and yellow vegetables and cancer incidence. These vegetables contain carotenoids, which are reported to exhibit anticarcinogenic effects. Overexpression of ErbB2 and ErbB3 genes is a frequent event in several human cancers. The present study was performed to determine whether $\alpha$-carotene, $\beta$-carotene, lutein, or lycopene inhibits cell growth and to assess such an effect is related to changes in the levels of the ErbB receptor family and tile ErbB3 receptor signaling pathway in HT-29 cells. HT-29 cells were cultured in serum-free medium in the presence of various concentrations (0~100 $\mu$M) of the individual carotenoids. $\alpha$ -Carotene and lycopene significantly inhibited cell growth in a dose-dependent manner, whereas lutein slightly inhibited cell growth and $\beta$-carotene increased cell growth. Lycopene is more potent than $\alpha$ -carotene in inhibiting HT-29 cell growth. Lycopene inhibited DNA synthesis and induced apoptosis of HT-29 cells. The ErbB3 ligand heregulin (HRG) increased cell growth but did not prevent the lycopene-induced inhibition of cell growth. Lycopene decreased ErbB2 protein levels in a dose-dependent manner. Immunoprecipitation/Western blot studies revealed that lycopene inhibited HRG-induced phosphorylation of ErbB3, recruitment of the 985 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) to the ErbB3 receptor, and phosphorylation of Akt. These results indicate that downregulation of ErbB2/ErbB3/PI3K/Akt signaling may be one of the mechanisms by which lycopene inhibits HT-29 cell pro-liferation and induces apoptosis.
Keywords
carotenoids; lycopene; ErbB; poptosis; DNA synthesis;
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1 Nicholson KM, Anderson NG. 2002. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14: 381-395.   DOI   ScienceOn
2 Ziegler RG, Colavito EA, Hartge P, McAdams MJ, Schoenberg JB, Mason TJ, Fraumeni JF Jr. 1996. Importance of alphacarotene, beta-carotene, and other phytochemicals in the etiology of lung cancer. J Natl Cancer Inst 88: 612-615.   DOI   ScienceOn
3 Kandel ES, Hay N. 1999. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res 253: 210-229.   DOI   ScienceOn
4 Ram TG, Hosick HL, Ethier SP. 2000. Heregulin-beta is especially potent in activating phosphatidylinositol 3-kinase in nontransformed human mammary epithelial cells. J Cell Physiol 183: 301-313.   DOI   ScienceOn
5 Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A, Fendly BM, Cerione RA, Vandlen RL, Carraway KL 3rd. 1994. Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 269: 14661-14665.
6 Tzahar E, Levkowitz G, Karunagaran D, Yi L, Peles E, Lavi S, Chang D, Liu N, Yayon A, Wen D. 1994. ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms. J Biol Chem 269: 25226-25233.
7 Motoyama AB, Hynes NE, Lane HA. 2002. The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. Cancer Res 62: 3151-3158.
8 Guy PM, Platko JV, Cantley LC, Cerione RA, Carraway KL 3rd. 1994. Insect cell-expressed p180 erbB3 possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci U S A 91: 8132-8136.   DOI   ScienceOn
9 Palozza P, Serini S, Maggiano N, Angelini M, Boninsegna A, Di Nicuolo F, Ranelletti FO, Calviello G. 2002. Induction of cell cycle arrest and apoptosis in human colon adenocarcinoma cell lines by beta-carotene through down-regulation of cyclin A and Bcl-2 family proteins. Carcinogenesis 23: 11-18.   DOI   ScienceOn
10 Zhang LX, Cooney RV, Bertram JS. 1991. Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemopreventive action. Carcinogenesis 12: 2109-2114.   DOI   ScienceOn
11 Amir H, Karas M, Giat J, Danilenko M, Levy R, Yermiahu T, Levy J, Sharoni Y. 1999. Lycopene and 1,25-dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells. Nutr Cancer 33: 105-112.   DOI   ScienceOn
12 Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF. 1989. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Sciences 244: 707-712.   DOI
13 Klippel A, Kavanaugh WM, Pot D, Williams LT. 1997. A specific product of phophatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol 17: 338-344.   DOI
14 Anderson NG, Ahmad T. 2002. ErbB receptor tyrosine ki-nase inhibitiors as therapeutic agents. Front Biosci 7: 1926-1940.   DOI
15 Salomon DS, Brandt R, Ciardiello F, Normanno N. 1995. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19: 183-232.   DOI   ScienceOn
16 Ziegler RG. 1991. Vegetables, fruits, and carotenoids and the risk of cancer. Am J Clin Nutr 53 (Suppl.): 251S-259S.   DOI
17 Toker A, Cantley LC. 1997. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387: 673-676.   DOI   ScienceOn
18 Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett WC. 1995. Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 87: 1767-1776.   DOI
19 Kotake-Nara E, Kushiro M, Zhang H, Sugawara T, Miyashita K, Nagao A. 2001.Carotenoids affect proliferation of human prostate cancer cells. J Nutr 131: 3303-3306.
20 Levy J, Bosin E, Feldman B, Giat Y, Miinster A, Danilenko M, Sharoni Y. 1995. Lycopene is a more potent inhibitor of human cancer cell proliferation than either alpha-carotene or beta-carotene. Nutr Cancer 24: 257-266.   DOI   ScienceOn
21 Kim D, Chung J. 2002. Akt: Versatile mediator of cell survival and beyond. J Biochem Mol Biol 35: 106-115.   과학기술학회마을   DOI
22 Safran H, Steinhoff M, Mangray S, Rathore R, King TC, Chai L, Berzein K, Moore T, Iannitti D, Reiss P, Pasquariello T, Akerman P, Quirk D, Mass R, Goldstein L, Tantravahi U. 2001. Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma. Am J Clin Oncol 24: 496-499.   DOI   ScienceOn
23 Denizot F, Lanf H. 1986. Rapid colorimetric assay for cell growth and survival modifications to the tetrazolium dye procedure giving improved sensivity and reliability. J Immunological Methods 89: 271-277.   DOI   ScienceOn
24 Varticovski L, Harrison-Findik D, Keeler ML, Susa M. 1994. Role of PI3-kinase in mitogenesis. Biochim Biophys Acta 1226: 1-11.   DOI   ScienceOn
25 Maurer CA, Friess H, Kretschmann B, Zimmermann A, Stauffer A, Baer HU, Korc M, Buchler MW. 1998. Increased expression of erbB3 in colorectal cancer is associated with concomitant increase in the level of erbB2. Hum Pathol 29: 771-777.   DOI   ScienceOn
26 Greenberg ER, Baron JA, Tosteson TD, Freeman DH, Beck GJ, Bond JH, Colacchio TA, Coller JA, Frankl HD, Haile RW, Mandel JS, Nierenberg DW, Rothstein R, Snover DC, Stevens MM, Summers RW, van Stolk RU, The Polps Prevention Study Group. 1994. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med 331: 141-147.   DOI   ScienceOn
27 Hellyer NJ, Kim HH, Greaves CH, Sierke SL, Koland JG. 1995. Cloning of the rat ErbB3 cDNA and characterization of the recombinant protein. Gene 165: 279-284.   DOI   ScienceOn
28 Goodman MT, Kolonel LN, Wilkens LR, Yoshizawa CN, Lemarchand L, Hankin JH. 1992. Dietary factors in lung cancer prognosis. Eur J Cancer 28: 495-501.   DOI   ScienceOn
29 Weisburger JH. 1991. Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants, and carotenoids. Am J Clin Nutr 53 (Suppl.): 226S-237S.   DOI
30 Alroy I, YardenY. 1997. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett 410: 83-86.   DOI   ScienceOn
31 Toyoda H, Komurasaki T, Ikeda Y, Yoshimoto M, Morimoto S. 1995. Molecular cloning of mouse epiregulin, a novel epidermal growth factor-related protein, expressed in the early stage of development. FEBS Lett 377: 403-407.   DOI   ScienceOn
32 Wang C-J, Lin J-K. 1989. Inhibitory effects of carotenoids and retinoids on the in vitro growth of rat C-6 glioma cells. Proc Natl Sci Counc Repub China B 13: 176-183.
33 Beta Carotene Cancer Prevention Study Group The Alphatocopherol. 1994. Effect of vitamin E and $\beta$-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330: 1029-1035.   DOI   ScienceOn
34 Kim DJ, Takasuka N, Kim JM, Sekine K, Ota T, Asamoto M, Murakoshi M, Nishino H, Nir Z, Tsuda H. 1997. Chemoprevention by lycopene of mouse lung neoplasia after combined initiation treatment with DEN, MNU and DMH. Cancer Lett 120: 15-22.   DOI   ScienceOn
35 Narisawa T, Fukaura Y, Hasebe M, Ito M, Aizawa R, Murakoshi M, Uemura S, Khachik F, Nishino H. 1996. Inhibitory effects of natural carotenoids, alpha-carotene, betacarotene, lycopene and lutein, on colonic aberrant crypt foci formation in rats. Cancer Lett 107: 137-142.   DOI   ScienceOn
36 Datta SR, Brunet A, Greenberg M. 1999 Cellular survival: a play in three Akts. Genes Dev 13: 2905-2927.   DOI   ScienceOn
37 Zhang SM, Tang GW, Russell RM, Mayzel KA, Stempfer MJ, Willet WC, Hunter DJ. 1997. Measurement of retinoids and carotenoids in breast adipose tissue and a comparision of concentrations in breast cancer cases and control subjects. Am J Clin Nutr 334: 626-632
38 Giovannucci E. 1999. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst 91: 317-331   DOI   ScienceOn
39 Doll R, Peto R. 1981. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 66: 1191-1308.
40 Blume-Jensen P, Hunter T. 2001. Oncogenic kinase signalling. Nature 411: 355-365.
41 Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R. 1996. Lack of effect of long-term supplementation with $\beta$-carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 334: 1145-1149.   DOI   ScienceOn