Effect of Lycopene on the Insulin-like Growth Factor-I Receptor Signaling Pathway in Human Colon Cancer HT-29 Cells

인간의 대장암 HT-29 세포주에서 라이코펜이 Insulin-like Growth Factor-I Receptor Signaling Pathway에 미치는 영향

  • ;
  • ;
  • ;
  • Frederick Khachik (Dept. of Chemistry & Biochemistry, Joint Institute for Food Safety & Applied Nutrition, University of Maryland) ;
  • 이현숙 (한림대학교 생명과학부 식품영양전공) ;
  • 정재인 (한림대학교 생명과학부 식품영양전공) ;
  • 강영희 (한림대학교 생명과학부 식품영양전공) ;
  • ;
  • 윤정한 (한림대학교 생명과학부 식품영양전공)
  • Published : 2003.04.01


Epidemiological data suggest that lycopene has anticancer activities in humans. Insulin-like growth factor-I receptor (IGF-IR) is a transmembrane tyrosine kinase that mediates the biological actions of IGFs and may play an active role in cancer progression. Because our previous in vitro studies have indicated lycopene inhibits HT-29 cell growth, the aim of this study was to determine whether lycopene induces apoptotic cell death and the inhibitory effect of lycopene on HT-29 cell growth is related to changes in IGF-IR levels and the receptor's intracellular signalling pathways. HT-29 cells were incubated for 4 days in serum-free medium in the presence of 0, 25, 50, or 100 $\mu$M lycopene, and the DNA fragmentation assay was performed. Cells treated with lycopene produced a distinct oligonucleosomal ladder with different sizes of DNA fragments, a typical characteristic of cells undergoing apoptosis. HT-29 cells were cultured for 4 days in serum-free medium in the presence of 0~100 $\mu$M lycopene and IGF-I (10nM) was added for 0~60 minutes immediately prior to lysate preparations. Western blot analysis of total lysates revealed that lycopene decreased the levels of IRS-1, Akt, phosphatidylinositol 3-kinase (PI3K), and IGF-IR $\beta$-subunit, and increased the levels of the IGF-IR precursor dose dependently. Lycopene also decreased IGF-I-induced phosphorylation of IGF-IR$\beta$, IRS-1 and Akt, which were, at least in part, due to decreased expression of these proteins. These results suggest that lycopene induces apoptosis of HT-29 cells by inhibiting IGF-IR signaling thereby interfering with an IGF-II-driven autocrine growth loop, which is known to exist in this cell line.


  1. Van Poppel G. 1993. Carotenoids and cancer: an update with emphasis on human intervention studies. Eur J Cancer 29A: 1335-1344.
  2. Hennekens CH, Burning JE, Manson JE, Stampfer M, Rosner B. 1996. Lack of effect of long-term effect of malignant neoplasms and cardiovascular disease. N Engl J Med 334: 1145-1149.
  3. Greenburg ER, Baron JA, Tosteson TD, Freeman DH, Beck GJ. 1994. Clinical trial of antioxidant vitamins to prevent colorectal adenomas. N Engl J Med 331: 141-147.
  4. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR. 1996. Effects of a combination of $\beta$-carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334: 1150-1155.
  5. Zhang SM, Tang GW, Russell RM, Mayzel KA, Stampfer MJ, Willett WC, Hunter DJ. 1997. Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer and control subjects. Am J Clin Nutr 66: 626-632.
  6. Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willet WC. 1995. Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 87: 1767-1776.
  7. Michaud DS, Feskanich D, Rimm EB, Colditz GA, Speizer FE, Willett WC, Giovannucci E. 2000. Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts. Am J Clin Nutr 72: 990-997.
  8. Giovannucci E. 1999. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst 59: 181-184.
  9. 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.
  10. 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.
  11. Sharoni Y, Giron E, Rise M, Levy J. 1997. Effects of lycopene enriched tomato oleoresin on 7,12-dimethylbenz[$\alpha$]anthracene-Copyright (C) 2005 NuriMedia Co., Ltd. induced rat mammary tumors. Cancer Detect Prev 21: 118-123.
  12. 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, $\beta$-carotene, lycopene and lutein, on colonic aberrant crypt foci formation in rats. Cancer Lett 107: 137-142.
  13. Jung JI, Khachik F, Kim EJ, Park JHY. 2002. Lycopene inhibits cell growth and decreases the level of ErbB2 and ErbB3 in human colon cancer HT-29 cells. Abstract No 735.2 presented at Experimental Biology 2002, New Orleans, Louisiana, USA.
  14. LeRoith D, Werner H, Beitner-Johnson D, Roberts CTJr. 1995. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16: 143-163.
  15. Alessi DR, Cohen P. 1998. Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev 8: 55-62.
  16. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD. 1997. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22: 267-272.
  17. Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J. 1998. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279: 563-566.
  18. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. 1998. Circulating concentrations of insulin-like growth factor I and risk of breast cancer. Lancet 351: 1393-1396.
  19. Guo Y, Narayan S, Yallampalli C, Singh P. 1992. Characterization of insulin like growth factor I receptors in human colon cancer. Gastroenterology 102: 1101-1108.
  20. Oh YS, Kim EJ, Schaffer BS, Kang YH, Binderup L, Macdonald RG, Park JHY. 2001. Synthetic low-calcaemic vitamin $D_3$ analogues inhibit secretion of insulin-like growth factor II and stimulate production of insulin-like growth factorbinding protein-6 in conjunction with growth suppression of HT-29 colon cancer cells. Mol Cell Endocrinol 183: 141-149.
  21. Khachik F, Steck A, Niggli US, Pfander H. 1998. Partial synthesis and structural elucidation of the oxidative metabolites of lycopene identified in tomato paste, tomoto juice, and human serum. J Agr Food Chem 46: 4874-4884.
  22. Goh ELK, Pircher RJ, Lobie PE. 1998. Growth hormone promotion of tibulin polymerization stabilized the microtubule network and protects against colchicin-induced apoptosis. Endocrinology 139: 4364-4372.
  23. Denizot F, Lang R. 1986. Rapid colorimetric assay for cell growth and survival modification to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunological Method 89: 271-277.
  24. Williams GM, Williams CL, Weisburger JH. 1999. Diet and cancer prevention: the fiber first diet. Toxicol Sci 52 (Suppl): 72-86.
  25. Agarwal S, Rao AV. 2000. Tomato lycopene and its role in human health and chronic diseases. CMAJ 163: 739-44.
  26. Agarwal S, Rao AV. 1998. Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study. Lipids 33: 981-984.
  27. Rao AV, Agarwal S. 1998. Bioavailability and in vivo antioxidant properties of lycopene from tomato products and their possible role in he prevention of cancer. Nutr Cancer 31: 199-203.
  28. Pool-Zobel BL, Bub A, Muller H, Wollowski I, Rechkemmer G. 1997. Consumption of vegetables reduces genetic damage in humans: first result of a human intervention trial with carotenoids-rich foods. Carcinogenesis 18: 1847-1850.
  29. Nahum A, Hirsch K, Danilenko M, Watts CKW, Prall OWJ, Levy J, Sharoni Y. 2001. Lycopene inhibition of cell cycle progression in breast and endothelial cancer cells is associated with reduction in cyclin D levels and retention of $p27^{kip1}$ in the cyclin E-cdk2 complexes. Oncogene 20: 3428-3436.
  30. Pommier GJ, Garrouste FL, el Atiq F, Roccabianca M, Marvaldi JL, Remacle-Bonnet MM. 1992. Potential autocrine role of insulin-like growth factor II during suramin-induced differentiation of HT29-D4 human colonic adenocarcinoma cell line. Cancer Res 52: 3182-3188.
  31. Karas M, Amir H, Fishman D, Danilenko M, Segal S, Nahum A, Koifmann A, Giat Y, Levy J, Sharoni Y. 2000. Lycopene Interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. Nutr Cancer 36: 101-111.

Cited by

  1. Anti-inflammatory effect of lycopene in SW480 human colorectal cancer cells vol.11, pp.2, 2017,
  2. Radial basis network analysis of color parameters to estimate lycopene content on tomato fruits vol.83, pp.1, 2010,
  3. Application of a UV–vis detection-HPLC method for a rapid determination of lycopene and β-carotene in vegetables vol.95, pp.2, 2006,
  4. Development and Validation of an UV-Visible Method for the Determination of β-Carotene in the Leafy Vegetables in Thailand vol.1033-1034, pp.1662-8985, 2014,