Please use this identifier to cite or link to this item:
標題: Role of lycopene in NADPH oxidase 4-mediated metastasis in human hepatocarcinoma SK-Hep-1 cells
蕃茄紅素在人類肝癌細胞 SK-Hep-1 中對於NADPH 氧化酶 4 調節之癌細胞轉移所扮演的角色
作者: Bo-Yi Jhou
關鍵字: Lycopene;NADPH oxidase 4;Metastasis;SK-Hep-1 cells;ROS;蕃茄紅素;NADPH 氧化酶 4;癌轉移;人類肝癌細胞;活性氧
引用: Spangenberg, H.C., R. Thimme, and H.E. Blum, Evolving therapies in the treatment of hepatocellular carcinoma. Biologics, 2008. 2(3): p. 453-62. Parkin, D.M., et al., Global cancer statistics, 2002. CA Cancer J Clin, 2005. 55(2): p. 74-108. El-Serag, H.B., Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol, 2002. 35(5 Suppl 2): p. S72-8. Okada, S., et al., Predictive factors for postoperative recurrence of hepatocellular carcinoma. Gastroenterology, 1994. 106(6): p. 1618-24. Nagao, T., et al., Postoperative recurrence of hepatocellular carcinoma. Ann Surg, 1990. 211(1): p. 28-33. Yamanaka, N., et al., Do the tumor cells of hepatocellular carcinomas dislodge into the portal venous stream during hepatic resection? Cancer, 1992. 70(9): p. 2263-7. Shirabe, K., et al., Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: univariate and multivariate analyses. Hepatology, 1991. 14(5): p. 802-5. Weinstat-Saslow, D. and P.S. Steeg, Angiogenesis and colonization in the tumor metastatic process: basic and applied advances. FASEB J, 1994. 8(6): p. 401-7. Steeg, P.S., Tumor metastasis: mechanistic insights and clinical challenges. Nat Med, 2006. 12(8): p. 895-904. Valastyan, S. and R.A. Weinberg, Tumor metastasis: molecular insights and evolving paradigms. Cell. 147(2): p. 275-92. Deryugina, E.I. and J.P. Quigley, Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev, 2006. 25(1): p. 9-34. Liotta, L.A., et al., Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature, 1980. 284(5751): p. 67-8. Parmo-Cabanas, M., et al., Role of metalloproteinases MMP-9 and MT1-MMP in CXCL12-promoted myeloma cell invasion across basement membranes. J Pathol, 2006. 208(1): p. 108-18. Bjorklund, M. and E. Koivunen, Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta, 2005. 1755(1): p. 37-69. Sier, C.F., et al., Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. Br J Cancer, 1996. 74(3): p. 413-7. Liabakk, N.B., et al., Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res, 1996. 56(1): p. 190-6. Hidalgo, M. and S.G. Eckhardt, Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst, 2001. 93(3): p. 178-93. Turrens, J.F., Mitochondrial formation of reactive oxygen species. J Physiol, 2003. 552(Pt 2): p. 335-44. Buffenstein, R., et al., The oxidative stress theory of aging: embattled or invincible? Insights from non-traditional model organisms. Age (Dordr), 2008. 30(2-3): p. 99-109. Fialkow, L., Y. Wang, and G.P. Downey, Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic Biol Med, 2007. 42(2): p. 153-64. Halliwell, B., J.M. Gutteridge, and C.E. Cross, Free radicals, antioxidants, and human disease: where are we now? J Lab Clin Med, 1992. 119(6): p. 598-620. Nishikawa, M., Reactive oxygen species in tumor metastasis. Cancer Lett, 2008. 266(1): p. 53-9. Loft, S. and H.E. Poulsen, Cancer risk and oxidative DNA damage in man. J Mol Med (Berl), 1996. 74(6): p. 297-312. Feig, D.I., T.M. Reid, and L.A. Loeb, Reactive oxygen species in tumorigenesis. Cancer Res, 1994. 54(7 Suppl): p. 1890s-1894s. Partridge, M., et al., Production of TGF-alpha and TGF-beta by cultured keratinocytes, skin and oral squamous cell carcinomas--potential autocrine regulation of normal and malignant epithelial cell proliferation. Br J Cancer, 1989. 60(4): p. 542-8. Moriai, T., et al., A variant epidermal growth factor receptor exhibits altered type alpha transforming growth factor binding and transmembrane signaling. Proc Natl Acad Sci U S A, 1994. 91(21): p. 10217-21. Centrella, M., et al., Transforming growth factor-beta gene family members and bone. Endocr Rev, 1994. 15(1): p. 27-39. Muraoka, R.S., et al., Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest, 2002. 109(12): p. 1551-9. Oft, M., K.H. Heider, and H. Beug, TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol, 1998. 8(23): p. 1243-52. McEarchern, J.A., et al., Invasion and metastasis of a mammary tumor involves TGF-beta signaling. Int J Cancer, 2001. 91(1): p. 76-82. Dunn, L.K., et al., Hypoxia and TGF-beta drive breast cancer bone metastases through parallel signaling pathways in tumor cells and the bone microenvironment. PLoS One, 2009. 4(9): p. e6896. Padua, D. and J. Massague, Roles of TGFbeta in metastasis. Cell Res, 2009. 19(1): p. 89-102. Otten, J., C. Bokemeyer, and W. Fiedler, Tgf-Beta superfamily receptors-targets for antiangiogenic therapy? J Oncol. 2010: p. 317068. Heldin, C.H., K. Miyazono, and P. ten Dijke, TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature, 1997. 390(6659): p. 465-71. Massague, J., TGF-beta signal transduction. Annu Rev Biochem, 1998. 67: p. 753-91. Groneberg, D.A., et al., Smads as intracellular mediators of airway inflammation. Exp Lung Res, 2004. 30(3): p. 223-50. Kretzschmar, M. and J. Massague, SMADs: mediators and regulators of TGF-beta signaling. Curr Opin Genet Dev, 1998. 8(1): p. 103-11. Wu, J.W., et al., Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling. Mol Cell, 2001. 8(6): p. 1277-89. Shi, Y., et al., A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature, 1997. 388(6637): p. 87-93. Itoh, F., et al., Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. EMBO J, 2001. 20(15): p. 4132-42. Wharton, K. and R. Derynck, TGFbeta family signaling: novel insights in development and disease. Development, 2009. 136(22): p. 3691-7. Moustakas, A., S. Souchelnytskyi, and C.H. Heldin, Smad regulation in TGF-beta signal transduction. J Cell Sci, 2001. 114(Pt 24): p. 4359-69. Maraldi, T., Natural compounds as modulators of NADPH oxidases. Oxid Med Cell Longev. 2013: p. 271602. Altenhofer, S., et al., The NOX toolbox: validating the role of NADPH oxidases in physiology and disease. Cell Mol Life Sci. 69(14): p. 2327-43. Paletta-Silva, R., N. Rocco-Machado, and J.R. Meyer-Fernandes, NADPH oxidase biology and the regulation of tyrosine kinase receptor signaling and cancer drug cytotoxicity. Int J Mol Sci. 14(2): p. 3683-704. Brown, D.I. and K.K. Griendling, Nox proteins in signal transduction. Free Radic Biol Med, 2009. 47(9): p. 1239-53. Takac, I., et al., The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J Biol Chem. 286(15): p. 13304-13. Miller, F.J., Jr., NADPH oxidase 4: walking the walk with Poldip2. Circ Res, 2009. 105(3): p. 209-10. Boudreau, H.E., et al., Nox4 involvement in TGF-beta and SMAD3-driven induction of the epithelial-to-mesenchymal transition and migration of breast epithelial cells. Free Radic Biol Med. 53(7): p. 1489-99. Cheng, G., et al., Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene, 2001. 269(1-2): p. 131-40. Chen, K., et al., Regulation of ROS signal transduction by NADPH oxidase 4 localization. J Cell Biol, 2008. 181(7): p. 1129-39. Block, K., Y. Gorin, and H.E. Abboud, Subcellular localization of Nox4 and regulation in diabetes. Proc Natl Acad Sci U S A, 2009. 106(34): p. 14385-90. Serrander, L., et al., NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. Biochem J, 2007. 406(1): p. 105-14. Zhang, B., Z. Liu, and X. Hu, Inhibiting cancer metastasis via targeting NAPDH oxidase 4. Biochem Pharmacol. 86(2): p. 253-66. Kumar, B., et al., Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res, 2008. 68(6): p. 1777-85. Yamaura, M., et al., NADPH oxidase 4 contributes to transformation phenotype of melanoma cells by regulating G2-M cell cycle progression. Cancer Res, 2009. 69(6): p. 2647-54. Graham, K.A., et al., NADPH oxidase 4 is an oncoprotein localized to mitochondria. Cancer Biol Ther. 10(3): p. 223-31. Weyemi, U., et al., Intracellular expression of reactive oxygen species-generating NADPH oxidase NOX4 in normal and cancer thyroid tissues. Endocr Relat Cancer. 17(1): p. 27-37. Xia, C., et al., Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res, 2007. 67(22): p. 10823-30. Shimada, K., et al., ROS generation via NOX4 and its utility in the cytological diagnosis of urothelial carcinoma of the urinary bladder. BMC Urol. 11: p. 22. Cucoranu, I., et al., NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res, 2005. 97(9): p. 900-7. Hu, T., et al., Reactive oxygen species production via NADPH oxidase mediates TGF-beta-induced cytoskeletal alterations in endothelial cells. Am J Physiol Renal Physiol, 2005. 289(4): p. F816-25. Diebold, I., et al., The NADPH oxidase subunit NOX4 is a new target gene of the hypoxia-inducible factor-1. Mol Biol Cell. 21(12): p. 2087-96. Moran, N.A. and T. Jarvik, Lateral transfer of genes from fungi underlies carotenoid production in aphids. Science. 328(5978): p. 624-7. Britton, G., Structure and properties of carotenoids in relation to function. FASEB J, 1995. 9(15): p. 1551-8. McNulty, H.P., et al., Differential effects of carotenoids on lipid peroxidation due to membrane interactions: X-ray diffraction analysis. Biochim Biophys Acta, 2007. 1768(1): p. 167-74. Armstrong, G.A. and J.E. Hearst, Carotenoids 2: Genetics and molecular biology of carotenoid pigment biosynthesis. FASEB J, 1996. 10(2): p. 228-37. Stahl, W. and H. Sies, Lycopene: a biologically important carotenoid for humans? Arch Biochem Biophys, 1996. 336(1): p. 1-9. Clinton, S.K., Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev, 1998. 56(2 Pt 1): p. 35-51. Olson, J.A. and N.I. Krinsky, Introduction: the colorful, fascinating world of the carotenoids: important physiologic modulators. FASEB J, 1995. 9(15): p. 1547-50. Mangels, A.R., et al., Carotenoid content of fruits and vegetables: an evaluation of analytic data. J Am Diet Assoc, 1993. 93(3): p. 284-96. Tonucci, L.H., et al., Carotenoid Content of Thermally Processed Tomato-Based Food Products. J Agric Food Chem, 1995. 43(3): p. 579–586. Boileau, T.W., A.C. Boileau, and J.W. Erdman, Jr., Bioavailability of all-trans and cis-isomers of lycopene. Exp Biol Med (Maywood), 2002. 227(10): p. 914-9. Miller, N.J., et al., Antioxidant activities of carotenes and xanthophylls. FEBS Lett, 1996. 384(3): p. 240-2. Conn, P.F., W. Schalch, and T.G. Truscott, The singlet oxygen and carotenoid interaction. J Photochem Photobiol B, 1991. 11(1): p. 41-7. Palozza, P., et al., Tomato lycopene and inflammatory cascade: basic interactions and clinical implications. Curr Med Chem. 17(23): p. 2547-63. Huang, C.S., et al., Anti-angiogenic effects of lycopene through immunomodualtion of cytokine secretion in human peripheral blood mononuclear cells. J Nutr Biochem. 24(2): p. 428-34. Khachik, F., G.R. Beecher, and J.C. Smith, Jr., Lutein, lycopene, and their oxidative metabolites in chemoprevention of cancer. J Cell Biochem Suppl, 1995. 22: p. 236-46. Stahl, W., et al., Stimulation of gap junctional communication: comparison of acyclo-retinoic acid and lycopene. Arch Biochem Biophys, 2000. 373(1): p. 271-4. Talalay, P., Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors, 2000. 12(1-4): p. 5-11. Levy, J., et al., Lycopene is a more potent inhibitor of human cancer cell proliferation than either alpha-carotene or beta-carotene. Nutr Cancer, 1995.24(3): p. 257-66. Chen, M.L., et al., Lycopene inhibits angiogenesis both in vitro and in vivo by inhibiting MMP-2/uPA system through VEGFR2-mediated PI3K-Akt and ERK/p38 signaling pathways. Mol Nutr Food Res. 56(6): p. 889-99. Huang, C.S., et al., Lycopene inhibits cell migration and invasion and upregulates Nm23-H1 in a highly invasive hepatocarcinoma, SK-Hep-1 cells. J Nutr, 2005. 135(9): p. 2119-23. Huang, C.S., J.W. Liao, and M.L. Hu, Lycopene inhibits experimental metastasis of human hepatoma SK-Hep-1 cells in athymic nude mice. J Nutr, 2008. 138(3): p. 538-43. Palozza, P., et al., Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis. 31(10): p. 1813-21. Mein, J.R., F. Lian, and X.D. Wang, Biological activity of lycopene metabolites: implications for cancer prevention. Nutr Rev, 2008. 66(12): p. 667-83. Yang, C.M., et al., Lycopene inhibits the proliferation of androgen-dependent human prostate tumor cells through activation of PPARgamma-LXRalpha-ABCA1 pathway. J Nutr Biochem. 23(1): p. 8-17. Yang, C.M., et al., Lycopene and the LXRalpha agonist T0901317 synergistically inhibit the proliferation of androgen-independent prostate cancer cells via the PPARgamma-LXRalpha-ABCA1 pathway. J Nutr Biochem. 23(9): p. 1155-62. Nahum, A., et al., Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27(Kip1) in the cyclin E-cdk2 complexes. Oncogene, 2001. 20(26): p. 3428-36. Heber, D. and Q.Y. Lu, Overview of mechanisms of action of lycopene. Exp Biol Med (Maywood), 2002. 227(10): p. 920-3. Livny, O., et al., Lycopene inhibits proliferation and enhances gap-junction communication of KB-1 human oral tumor cells. J Nutr, 2002. 132(12): p. 3754-9. Ghosh, B. and I. Bose, Gene copy number and cell cycle arrest. Phys Biol, 2006. 3(1): p. 29-36. Nelson, D.L. and M.M. Cox, Lehninger Principles of Biochemistry 4th edition. 2005: p. 472-473. Park, Y.O., E.S. Hwang, and T.W. Moon, The effect of lycopene on cell growth and oxidative DNA damage of Hep3B human hepatoma cells. Biofactors, 2005. 23(3): p. 129-39. Ivanov, N.I., et al., Lycopene differentially induces quiescence and apoptosis in androgen-responsive and -independent prostate cancer cell lines. Clin Nutr, 2007. 26(2): p. 252-63. Nahum, A., et al., Lycopene inhibition of IGF-induced cancer cell growth depends on the level of cyclin D1. Eur J Nutr, 2006. 45(5): p. 275-82. Alberts, B., A. Johnson, and J. Lewis, Molecular Biology of the Cell 4th edition. 2002. Hantz, H.L., L.F. Young, and K.R. Martin, Physiologically attainable concentrations of lycopene induce mitochondrial apoptosis in LNCaP human prostate cancer cells. Exp Biol Med (Maywood), 2005. 230(3): p. 171-9. Kanagaraj, P., et al., Effect of lycopene on insulin-like growth factor-I, IGF binding protein-3 and IGF type-I receptor in prostate cancer cells. J Cancer Res Clin Oncol, 2007. 133(6): p. 351-9. Salman, H., et al., Lycopene affects proliferation and apoptosis of four malignant cell lines. Biomed Pharmacother, 2007. 61(6): p. 366-9. Martin, P.E. and W.H. Evans, Incorporation of connexins into plasma membranes and gap junctions. Cardiovasc Res, 2004. 62(2): p. 378-87. Musil, L.S., et al., Regulation of connexin degradation as a mechanism to increase gap junction assembly and function. J Biol Chem, 2000. 275(33): p. 25207-15. Trosko, J.E. and R.J. Ruch, Gap junctions as targets for cancer chemoprevention and chemotherapy. Curr Drug Targets, 2002. 3(6): p. 465-82. Yamasaki, H., Role of disrupted gap junctional intercellular communication in detection and characterization of carcinogens. Mutat Res, 1996. 365(1-3): p. 91-105. Yamasaki, H. and C.C. Naus, Role of connexin genes in growth control. Carcinogenesis, 1996. 17(6): p. 1199-213. McLachlan, E., Q. Shao, and D.W. Laird, Connexins and gap junctions in mammary gland development and breast cancer progression. J Membr Biol, 2007. 218(1-3): p. 107-21. King, T.J. and J.S. Bertram, Connexins as targets for cancer chemoprevention and chemotherapy. Biochim Biophys Acta, 2005. 1719(1-2): p. 146-60. Fornelli, F., et al., The influence of lycopene on the proliferation of human breast cell line (MCF-7). Toxicol In Vitro, 2007. 21(2): p. 217-23. Chalabi, N., et al., Expression profiling by whole-genome microarray hybridization reveals differential gene expression in breast cancer cell lines after lycopene exposure. Biochim Biophys Acta, 2007. 1769(2): p. 124-30. Saxena, N., et al., RAS: target for cancer therapy. Cancer Invest, 2008. 26(9): p. 948-55. Swyer, G.I.M., The cholesterol content of normal and enlarged prostates. Cancer Res , 1942. 2: p. 372-5. Hager, M.H., K.R. Solomon, and M.R. Freeman, The role of cholesterol in prostate cancer. Curr Opin Clin Nutr Metab Care, 2006. 9(4): p. 379-85. Matsuyama, M. and R. Yoshimura, Peroxisome Proliferator-Activated Receptor-gamma Is a Potent Target for Prevention and Treatment in Human Prostate and Testicular Cancer. PPAR Res, 2008. 2008: p. 249849. Fukuchi, J., et al., Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells. Cancer Res, 2004. 64(21): p. 7686-9. Kozuki, Y., Y. Miura, and K. Yagasaki, Inhibitory effects of carotenoids on the invasion of rat ascites hepatoma cells in culture. Cancer Lett, 2000. 151(1): p. 111-5. Huang, C.S., et al., Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1. J Nutr Biochem, 2007. 18(7): p. 449-56. Hwang, E.S. and H.J. Lee, Inhibitory effects of lycopene on the adhesion, invasion, and migration of SK-Hep1 human hepatoma cells. Exp Biol Med (Maywood), 2006. 231(3): p. 322-7. Lin, M.C., et al., Cancer chemopreventive effects of lycopene: suppression of MMP-7 expression and cell invasion in human colon cancer cells. J Agric Food Chem. 59(20): p. 11304-18. Wright, T.J., et al., Dynamics of vascular endothelial-cadherin and beta-catenin localization by vascular endothelial growth factor-induced angiogenesis in human umbilical vein cells. Exp Cell Res, 2002. 280(2): p. 159-68. Karamysheva, A.F., Mechanisms of angiogenesis. Biochemistry (Mosc), 2008. 73(7): p. 751-62. Neufeld, G., et al., Vascular endothelial growth factor (VEGF) and its receptors. FASEB J, 1999. 13(1): p. 9-22. Folkman, J., Angiogenesis. Annu Rev Med, 2006. 57: p. 1-18. Ferrara, N. and R.S. Kerbel, Angiogenesis as a therapeutic target. Nature, 2005. 438(7070): p. 967-74. Sahin, M., E. Sahin, and S. Gumuslu, Effects of lycopene and apigenin on human umbilical vein endothelial cells in vitro under angiogenic stimulation. Acta Histochem. 114(2): p. 94-100. Elgass, S., A. Cooper, and M. Chopra, Lycopene inhibits angiogenesis in human umbilical vein endothelial cells and rat aortic rings. Br J Nutr. 108(3): p. 431-9. Morton, C.L. and P.J. Houghton, Establishment of human tumor xenografts in immunodeficient mice. Nat Protoc, 2007. 2(2): p. 247-50. Tang, L., et al., Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr, 2005. 135(2): p. 287-90. Yang, C.M., et al., Growth inhibitory efficacy of lycopene and beta-carotene against androgen-independent prostate tumor cells xenografted in nude mice. Mol Nutr Food Res. 55(4): p. 606-12. Tang, F.Y., M.H. Pai, and X.D. Wang, Consumption of lycopene inhibits the growth and progression of colon cancer in a mouse xenograft model. J Agric Food Chem. 59(16): p. 9011-21. Khanna, C. and K. Hunter, Modeling metastasis in vivo. Carcinogenesis, 2005. 26(3): p. 513-23. Kim, D.J., et al., Chemoprevention by lycopene of mouse lung neoplasia after combined initiation treatment with DEN, MNU and DMH. Cancer Lett, 1997. 120(1): p. 15-22. Gupta, P., M.P. Bansal, and A. Koul, Spectroscopic characterization of lycopene extract from Lycopersicum esculentum (Tomato) and its evaluation as a chemopreventive agent against experimental hepatocarcinogenesis in mice. Phytother Res. 27(3): p. 448-56. Auerbach, R., et al., Angiogenesis assays: a critical overview. Clin Chem, 2003. 49(1): p. 32-40. Ribatti, D., et al., The chick embryo chorioallantoic membrane as a model for in vivo research on angiogenesis. Int J Dev Biol, 1996. 40(6): p. 1189-97. Staton, C.A., et al., Current methods for assaying angiogenesis in vitro and in vivo. Int J Exp Pathol, 2004. 85(5): p. 233-48. Giovannucci, E., A review of epidemiologic studies of tomatoes, lycopene, and prostate cancer. Exp Biol Med (Maywood), 2002. 227(10): p. 852-9. Jain, M.G., et al., Plant foods, antioxidants, and prostate cancer risk: findings from case-control studies in Canada. Nutr Cancer, 1999. 34(2): p. 173-84. Giovannucci, E., et al., Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst, 1995. 87(23): p. 1767-76. Burney, P.G., G.W. Comstock, and J.S. Morris, Serologic precursors of cancer: serum micronutrients and the subsequent risk of pancreatic cancer. Am J Clin Nutr, 1989. 49(5): p. 895-900. Franceschi, S., et al., Tomatoes and risk of digestive-tract cancers. Int J Cancer, 1994. 59(2): p. 181-4. Bond, G.G., F.E. Thompson, and R.R. Cook, Dietary vitamin A and lungcancer: results of a case-control study among chemical workers. Nutr Cancer, 1987. 9(2-3): p. 109-21. Le Marchand, L., et al., Vegetable consumption and lung cancer risk: a population-based case-control study in Hawaii. J Natl Cancer Inst, 1989. 81(15): p. 1158-64. Harris, R.W., et al., A case-control study of dietary carotene in men with lung cancer and in men with other epithelial cancers. Nutr Cancer, 1991. 15(1): p. 63-8. Nkondjock, A., et al., Dietary intake of lycopene is associated with reduced pancreatic cancer risk. J Nutr, 2005. 135(3): p. 592-7. Dorgan, J.F., et al., Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control, 1998. 9(1): p. 89-97. Tsugane, S., et al., Cross-sectional study with multiple measurements of biological markers for assessing stomach cancer risks at the population level. Environ Health Perspect, 1992. 98: p. 207-10. Bunker, C.H., et al., A randomized trial of lycopene supplementation in Tobago men with high prostate cancer risk. Nutr Cancer, 2007. 57(2): p. 130-7. Clark, P.E., et al., Phase I-II prospective dose-escalating trial of lycopene in patients with biochemical relapse of prostate cancer after definitive local therapy. Urology, 2006. 67(6): p. 1257-61. Kucuk, O., et al., Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev, 2001. 10(8): p. 861-8. Brieger, K., et al., Reactive oxygen species: from health to disease. Swiss Med Wkly. 142: p. w13659. Lin, C.Y., C.S. Huang, and M.L. Hu, The use of fetal bovine serum as delivery vehicle to improve the uptake and stability of lycopene in cell culture studies. Br J Nutr, 2007. 98(1): p. 226-32. Repesh, L.A., A new in vitro assay for quantitating tumor cell invasion. Invasion Metastasis, 1989. 9(3): p. 192-208. Yang, C.M., et al., The in vitro and in vivo anti-metastatic efficacy of oxythiamine and the possible mechanisms of action. Clinical & Experimental Metastasis, 2010. 27(5): p. 341-349. Thannickal, V.J. and B.L. Fanburg, Activation of an H2O2-generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1. J Biol Chem, 1995. 270(51): p. 30334-8. Kleiner, D.E. and W.G. Stetler-Stevenson, Quantitative zymography: detection of picogram quantities of gelatinases. Anal Biochem, 1994. 218(2): p. 325-9. Borbely, G., et al., Small-molecule inhibitors of NADPH oxidase 4. J Med Chem. 53(18): p. 6758-62. Shao, A. and J.N. Hathcock, Risk assessment for the carotenoids lutein and lycopene. Regul Toxicol Pharmacol, 2006. 45(3): p. 289-98. Carmona-Cuenca, I., et al., Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity. J Hepatol, 2008. 49(6): p. 965-76. Palozza, P., et al., beta-carotene at high concentrations induces apoptosis by enhancing oxy-radical production in human adenocarcinoma cells. Free Radic Biol Med, 2001. 30(9): p. 1000-7. Mayne, S.T., et al., Plasma lycopene concentrations in humans are determined by lycopene intake, plasma cholesterol concentrations and selected demographic factors. J Nutr, 1999. 129(4): p. 849-54. Ford, E.S., Variations in serum carotenoid concentrations among United States adults by ethnicity and sex. Ethn Dis, 2000. 10(2): p. 208-17. Khachik, F., et al., Chemistry, distribution, and metabolism of tomato carotenoids and their impact on human health. Exp Biol Med (Maywood), 2002. 227(10): p. 845-51. Pierce, J.P., et al., Increases in plasma carotenoid concentrations in response to a major dietary change in the women's healthy eating and living study. Cancer Epidemiol Biomarkers Prev, 2006. 15(10): p. 1886-92.
NADPH 氧化酶 4 (NADPH oxidase 4, NOX4)具有產生活性氧(reactive oxygenspecies, ROS)的功能,且與癌細胞轉移呈正相關。臨床研究已經指出,相對於使用抗氧化劑療法,針對能產生 ROS 的酵素作為標靶對於治療由過量 ROS 所引起的癌症可能是較好的方法。先前研究發現,在人類肝癌細胞株 SK-Hep-1 中,蕃茄紅素具有降低 ROS 的生成以及抑制癌細胞轉移的能力。然而,NOX4 在蕃茄紅素的抗癌轉移作用中所扮演的角色目前仍不清楚。在本篇研究中,我們首先驗證了本研究室先前的結果,亦即:蕃茄紅素(0.1-5 μM)與 SK-Hep-1 細胞培養 2-12小時後,可顯著地抑制細胞移行、侵襲以及黏附的能力;在培養 24 小時後,可顯著地抑制細胞基質金屬蛋白酶(matrix metalloproteinase, MMP)-9 和-2 的酵素活性;在培養 0.5-6 小時後,可顯著地降低細胞內 ROS 的產生。我們也首次發現,蕃茄紅素(0.1-5 μM)與 SK-Hep-1 細胞培養 2 小時後,可顯著地抑制 NOX4 的蛋白質表現及 NADPH 氧化酶活性,以及抑制 mothers against decapentaplegic 2/3(SMAD2/3)的蛋白質表現。接著,我們使用 NOX4 之非特異性抑制劑diphenyleneiodonium (DPI)與蕃茄紅素合併培養細胞,以確認 NOX4 在蕃茄紅素的抗癌轉移作用中所扮演的角色。結果顯示,合併使用低濃度的 DPI 與蕃茄紅素對於細胞的移行能力 MMP-9 和 MMP-2 的酵素活性以及 NADPH 氧化酶活性、具有更強的抑制效果,意味著 NOX4 可能參與了蕃茄紅素的抗癌轉移作用。我們更進一步地探討蕃茄紅素對於由轉化生長因子(transforming growth factor-β,TGF-β)所誘發之癌轉移所造成的影響,以確認 NOX4 在蕃茄紅素所調節的癌轉移中所扮演的角色。結果顯示 TGF-β (5 ng/mL)可顯著地促進細胞移行、侵襲及黏附能力,並且增加細胞內 ROS 生成、促進 MMP-9 及 MMP-2 酵素活性、促進NOX4 的蛋白質表現、NADPH 氧化酶活性,以及促進 SMAD2/3 的蛋白質表現。當細胞與 TGF-β 及蕃茄紅素(2.5 μM)兩者合併培養之後 這些由 TGF-β 所造成的,改變則可以被蕃茄紅素所逆轉。最後,我們將 SK-Hep-1 細胞中 NOX4 表現利用短暫性轉染 siRNA 使其靜默化,結果發現,相對於沒有將 NOX4 基因靜默化的控制組,NOX4 基因靜默化後可以完全抵消蕃茄紅素、TGF-β 以及兩者合併使用對於細胞移行能力、NOX4 和 SMAD2/3 蛋白質表現的影響,並且削弱 MMP-9和 MMP-2 的酵素活性。以上結果說明,TGF-β 所誘發之 NOX4-ROS-SMAD2/3訊息傳遞路徑參與了蕃茄紅素抑制人類肝癌細胞株 SK-Hep-1 癌轉移的作用。

NADPH oxidase 4 (NOX4) with the sole function to produce reactive oxygen species (ROS) has been shown to be positively associated with cancer metastasis. Clinical studies have indicated that, relative to antioxidant therapy, targeting ROS-producing enzymes may be a more beneficial strategy to combat cancers caused by excess ROS. Lycopene has been shown to attenuate ROS production and inhibit tumor metastasis in human hepatocarcinoma SK-Hep-1 cells. However, the role of NOX4 in the anti-metastatic action of lycopene remains unknown. Herein, we first confirmed the inhibitory effect of lycopene on the metastasis in SK-Hep-1 cells by showing that treatment of lycopene (0.1-5 μM) significantly inhibited migration, invasion and adhesion at 2-12 h of incubation, suppressed activities of matrix metalloproteinase (MMP)-9, -2 at 24 h of incubation, and decreased intracellular ROS production at 0.5-6 h of incubation. We found for the first time that lycopene (0.1-5 μM) significantly inhibited NOX4 protein expression, NADPH oxidase activity, and mothers against decapentaplegic 2/3 (SMAD2/3) protein expression at 2 h of incubation. We then used diphenyleneiodonium (DPI), the most widely used NOX4 non-specific inhibitor, in combination with lycopene to confirm the role of NOX4 in the anti-metastatic actions of lycopene. Results reveal that relative low levels of DPI in combination with lycopene exhibited stronger inhibition of migration, MMP-9 and MMP-2 activities, and NADPH oxidase activity, suggesting that NOX4 may be involved in the anti-metastatic effects of lycopene. We further determined the effects of lycopene on transforming growth factor β (TGF-β)-induced metastasis to confirm the role of NOX4 on lycopene-mediated cancer metastasis. Results reveal that TGF-β (5 ng/mL) significantly increased migration, invasion, adhesion, intracellular ROS production, MMP-9 and MMP-2 activities, NOX4 protein expression, NADPH oxidase activity and SMAD2/3 protein expression. These changes caused by TGF-βwere completely reversed by pre-incubation of SK-Hep-1 cells with lycopene (2.5 μM). Using transient transfection of siRNA against NOX4, we found that NOX4 knockdown completely abolished the effects of lycopene, TGF-β and the combined treatment on migration, NOX4 and SMAD2/3 protein expression as well as partially decreased activities of MMP-9 and MMP-2, as compared to non-silencing group. Overall, the present results demonstrate that the NOX4-ROS-SMAD2/3 pathway that is known to be induced by TGF-β is involved in the anti-metastatic action of lycopene in human hepatocarcinoma SK-Hep-1 cells.
Rights: 同意授權瀏覽/列印電子全文服務,2018-07-15起公開。
Appears in Collections:食品暨應用生物科技學系

Files in This Item:
File SizeFormat Existing users please Login
nchu-103-7101043027-1.pdf2.48 MBAdobe PDFThis file is only available in the university internal network   
Show full item record

Google ScholarTM


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.