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研究生:陳裕仁
研究生(外文):Yu-Jen
論文名稱:沒食子酸透過脂肪酸合成酶調控p27抑制乳癌細胞生長之作用
論文名稱(外文):Gallic acid regulates p27 by Fas to suppress breast cancer cell proliferation
指導教授:許振東許振東引用關係
指導教授(外文):Jeng-Dong Hsu
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:生化暨生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:80
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  • 被引用被引用:1
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關於天然物抗癌的研究是最近的新潮流,因為傳統化療的副作用太大,所以癌症病患往往不能真正受益,因此開發天然物之活性分性析為目前研究之標的。而沒食子酸(GA)為一天然具抗氧化能力的多酚類。可在五倍子、漆樹、金縷梅、茶葉、橡樹皮和其它植物中發現。且被證實對癌細胞會有毒性反應,但並不會傷害到健康的細胞。文獻中也指出,沒食子酸會抑制細胞增生、抗氧化及抗過敏等。乳癌的早期診斷是乳癌治療的目標之一,研究也證實早期診斷不僅可降低乳癌發生率及死亡率,也可以大大的改善治療的選擇,更可以提高治癒的成功率。在本篇研究,我們以沒食子酸為研究題材,探討沒食子酸是否具有抑制乳癌細胞生長的能力。我們首先以沒食子酸處理乳癌細胞株MCF-7後,以MTT方法檢測細胞增生,發現沒食子酸能有效抑制乳癌細胞株MCF-7增生。再以流式細胞儀檢測細胞週期,結果乳癌細胞株MCF-7在經過沒食子酸處理後,細胞週期發生G2/M期停滯。此外,我們更進一步採用西方墨點法測量cyclinB1、cdc2、cyclinA、cdk2、p21、p27、Fas和skp2這些與細胞週期中G2/M期相關蛋白質的表現情形,結果發現p21、p27等週期蛋白依賴激酶抑制因子和Fas蛋白,在乳癌細胞株MCF-7處理沒食子酸後,均有上昇的趨勢。綜合以上實驗結果顯示,沒食子酸可以抑制乳癌細胞株MCF-7增生,其機制與G2/M停滯、Fas調控p21、p27表現量上升有關。

Accumulating evidence indicates that the importance of compounds derived from natural products to treat human diseases.Gallic acid is a naturally occurring polyphenol with antioxidant capacity. It was found in gallnuts, sumac, witch hazel, tea leaves, oak bark, and other plants. And gallic acid was found to show cytotoxicity against cancer cells, without harming healthy cells, and it has been reported to suppress cell proliferation, the oxidation resistance and the anti-allergy etc.Early detection is regarded as the best defense of medical intervention against breast cancer. Studies have reported that eraly diagnosis is one of the most effective ways to reduce incidence and death rates of breast cancer. In this study, we focus on the anti-tumor effect of gallic acid. First, we treated gallic acid with breast cancer cell line MCF-7, then we detected the proliferation by MTT assay, we found gallic acid could inhibit the proliferation of MCF-7 cell.Second, we observed cell cycle by flow cytometer. We found that the extract of gallic acid could arrest MCF-7 cell cycle on the G2/M phase. Furthermore, we used western blot to assay the concentration discrepancy of G2/M phase-associate proteins cyclinB1, cdc2, cyclinA, cdk2, p21, p27, Fas and skp2. We found that p21, p27 and Fas have significant elevation during gallic acid treatment. In conclusion, gallic acid can inhibit proliferation of human breast cancer cell line MCF-7 through arresting G2/M phase and up-regulating of expression of CKIs, especially p21 and p27, by Fas.

壹、 中英文摘要....................................1
貳、 縮寫檢索表....................................5
參、 序論..........................................6
肆、 研究動機......................................23
伍、 實驗方法與材料................................24
陸、 實驗結果......................................33
柒、 討論..........................................38
捌、 參考文獻......................................43
玖、 圖表與圖表說明................................49
拾、 附圖表........................................62



1.de Bock, G.H., et al., A family history of breast cancer will not predict female early onset breast cancer in a population-based setting. BMC Cancer, 2008. 8: p. 203.
2.Yip, C.H., Breast cancer in Asia. Methods Mol Biol, 2009. 471: p. 51-64.
3.Cancer, C.G.o.H.F.i.B., Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet, 2001. 358(9291): p. 1389-99.
4.Pharoah, P.D., et al., Family history and the risk of breast cancer: a systematic review and meta-analysis. Int J Cancer, 1997. 71(5): p. 800-9.
5.Conway, K., et al., Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutation. Breast Cancer Res, 2007. 9(3): p. R36.
6.Coleman, R.E., Current and future status of adjuvant therapy for breast cancer. Cancer, 2003. 97(3 Suppl): p. 880-6.
7.Hamdi, M., et al., The role of oncoplastic surgery in breast cancer. Acta Chir Belg, 2008. 108(6): p. 666-72.
8.Dickler, A., O. Ivanov, and D. Francescatti, Intraoperative radiation therapy in the treatment of early-stage breast cancer utilizing xoft axxent electronic brachytherapy. World J Surg Oncol, 2009. 7: p. 24.
9.Breckwoldt, M. and U. Karck, Tamoxifen for breast cancer prevention. Exp Clin Endocrinol Diabetes, 2000. 108(4): p. 243-6.
10.Burckhardt, P., [Selective estrogen receptor modulators (SERM): new substances for hormone replacement therapy]. Schweiz Med Wochenschr, 1999. 129(49): p. 1926-30.
11.Cykert, S., Tamoxifen for breast-cancer prevention. Lancet, 2003. 361(9352): p. 177; author reply 178.
12.Wolczynski, S., et al., [Biochemical mechanism of raloxifen and tamoxifen action for the prevention of breast cancer. Studies in vitro]. Ginekol Pol, 2000. 71(9): p. 1147-52.
13.Newman, W.G., et al., Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res, 2008. 14(18): p. 5913-8.
14.Shepard, H.M., et al., Herceptin. Handb Exp Pharmacol, 2008(181): p. 183-219.
15.Pal, S.K. and M. Pegram, HER2 targeted therapy in breast cancer...beyond Herceptin. Rev Endocr Metab Disord, 2007. 8(3): p. 269-77.
16.Schiff, P.B., J. Fant, and S.B. Horwitz, Promotion of microtubule assembly in vitro by taxol. Nature, 1979. 277(5698): p. 665-7.
17.Savi, L.A., et al., Evaluation of anti-herpetic and antioxidant activities, and cytotoxic and genotoxic effects of synthetic alkyl-esters of gallic acid. Arzneimittelforschung, 2005. 55(1): p. 66-75.
18.Hsieh, C.L. and G.C. Yen, Antioxidant actions of du-zhong (Eucommia ulmoides Oliv.) toward oxidative damage in biomolecules. Life Sci, 2000. 66(15): p. 1387-400.
19.Perchellet, J.P., et al., Antitumor-promoting activities of tannic acid, ellagic acid, and several gallic acid derivatives in mouse skin. Basic Life Sci, 1992. 59: p. 783-801.
20.Inoue, M., et al., Antioxidant, gallic acid, induces apoptosis in HL-60RG cells. Biochem Biophys Res Commun, 1994. 204(2): p. 898-904.
21.Inoue, M., et al., Selective induction of cell death in cancer cells by gallic acid. Biol Pharm Bull, 1995. 18(11): p. 1526-30.
22.Madlener, S., et al., Gallic acid inhibits ribonucleotide reductase and cyclooxygenases in human HL-60 promyelocytic leukemia cells. Cancer Lett, 2007. 245(1-2): p. 156-62.
23.Ohno, T., M. Inoue, and Y. Ogihara, Cytotoxic activity of gallic acid against liver metastasis of mastocytoma cells P-815. Anticancer Res, 2001. 21(6A): p. 3875-80.
24.Ohno, Y., et al., Induction of apoptosis by gallic acid in lung cancer cells. Anticancer Drugs, 1999. 10(9): p. 845-51.
25.Yoshioka, K., et al., Induction of apoptosis by gallic acid in human stomach cancer KATO III and colon adenocarcinoma COLO 205 cell lines. Oncol Rep, 2000. 7(6): p. 1221-3.
26.Veluri, R., et al., Fractionation of grape seed extract and identification of gallic acid as one of the major active constituents causing growth inhibition and apoptotic death of DU145 human prostate carcinoma cells. Carcinogenesis, 2006. 27(7): p. 1445-53.
27.Sutra, T., et al., Preventive effects of nutritional doses of polyphenolic molecules on cardiac fibrosis associated with metabolic syndrome: involvement of osteopontin and oxidative stress. J Agric Food Chem, 2008. 56(24): p. 11683-7.
28.Lee, J.S., et al., Fatty acid synthase inhibition by amentoflavone induces apoptosis and antiproliferation in human breast cancer cells. Biol Pharm Bull, 2009. 32(8): p. 1427-32.
29.Okawa, Y., et al., Fatty acid synthase is a novel therapeutic target in multiple myeloma. Br J Haematol, 2008. 141(5): p. 659-71.
30.Puig, T., et al., Green tea catechin inhibits fatty acid synthase without stimulating carnitine palmitoyltransferase-1 or inducing weight loss in experimental animals. Anticancer Res, 2008. 28(6A): p. 3671-6.
31.Schafer, K.A., The cell cycle: a review. Vet Pathol, 1998. 35(6): p. 461-78.
32.Tashima, Y., et al., Prediction of key factor controlling G1/S phase in the mammalian cell cycle using system analysis. J Biosci Bioeng, 2008. 106(4): p. 368-74.
33.Vermeulen, K., D.R. Van Bockstaele, and Z.N. Berneman, The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif, 2003. 36(3): p. 131-49.
34.Smith, M.L. and A.J. Fornace, Jr., Mammalian DNA damage-inducible genes associated with growth arrest and apoptosis. Mutat Res, 1996. 340(2-3): p. 109-24.
35.Delaval, B. and D. Birnbaum, A cell cycle hypothesis of cooperative oncogenesis (Review). Int J Oncol, 2007. 30(5): p. 1051-8.
36.Sanchez, I. and B.D. Dynlacht, New insights into cyclins, CDKs, and cell cycle control. Semin Cell Dev Biol, 2005. 16(3): p. 311-21.
37.Sherr, C.J., G1 phase progression: cycling on cue. Cell, 1994. 79(4): p. 551-5.
38.Hunter, T. and J. Pines, Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell, 1994. 79(4): p. 573-82.
39.Koepp, D.M., J.W. Harper, and S.J. Elledge, How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell, 1999. 97(4): p. 431-4.
40.Lees, E.M. and E. Harlow, Sequences within the conserved cyclin box of human cyclin A are sufficient for binding to and activation of cdc2 kinase. Mol Cell Biol, 1993. 13(2): p. 1194-201.
41.De Luca, A., et al., Cyclin T: three forms for different roles in physiological and pathological functions. J Cell Physiol, 2003. 194(2): p. 101-7.
42.Baek, K., et al., Crystal structure of human cyclin K, a positive regulator of cyclin-dependent kinase 9. J Mol Biol, 2007. 366(2): p. 563-73.
43.Coverley, D., H. Laman, and R.A. Laskey, Distinct roles for cyclins E and A during DNA replication complex assembly and activation. Nat Cell Biol, 2002. 4(7): p. 523-8.
44.Nurse, P., Universal control mechanism regulating onset of M-phase. Nature, 1990. 344(6266): p. 503-8.
45.Tashiro, E., A. Tsuchiya, and M. Imoto, Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression. Cancer Sci, 2007. 98(5): p. 629-35.
46.Weinberg, R.A., The retinoblastoma protein and cell cycle control. Cell, 1995. 81(3): p. 323-30.
47.Lundberg, A.S. and R.A. Weinberg, Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol, 1998. 18(2): p. 753-61.
48.Miele, A., et al., HiNF-P directly links the cyclin E/CDK2/p220NPAT pathway to histone H4 gene regulation at the G1/S phase cell cycle transition. Mol Cell Biol, 2005. 25(14): p. 6140-53.
49.Welcker, M., et al., Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation. Mol Cell, 2003. 12(2): p. 381-92.
50.Guo, Z. and J.W. Stiller, Comparative genomics of cyclin-dependent kinases suggest co-evolution of the RNAP II C-terminal domain and CTD-directed CDKs. BMC Genomics, 2004. 5(1): p. 69.
51.Malumbres, M. and M. Barbacid, To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer, 2001. 1(3): p. 222-31.
52.Nabel, E.G., CDKs and CKIs: molecular targets for tissue remodelling. Nat Rev Drug Discov, 2002. 1(8): p. 587-98.
53.Brooks, G., Cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors: detection methods and activity measurements. Methods Mol Biol, 2005. 296: p. 291-8.
54.Li, J.M. and G. Brooks, Cell cycle regulatory molecules (cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors) and the cardiovascular system; potential targets for therapy? Eur Heart J, 1999. 20(6): p. 406-20.
55.Hannon, G.J. and D. Beach, p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature, 1994. 371(6494): p. 257-61.
56.Serrano, M., G.J. Hannon, and D. Beach, A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature, 1993. 366(6456): p. 704-7.
57.Hirai, H., et al., Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol, 1995. 15(5): p. 2672-81.
58.Chan, F.K., et al., Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. Mol Cell Biol, 1995. 15(5): p. 2682-8.
59.Sherr, C.J. and J.M. Roberts, CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev, 1999. 13(12): p. 1501-12.
60.Xu, K., et al., Protein-protein interactions involved in the recognition of p27 by E3 ubiquitin ligase. Biochem J, 2003. 371(Pt 3): p. 957-64.
61.Pagano, M., et al., Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science, 1995. 269(5224): p. 682-5.
62.Schneider, G., et al., IKKalpha controls p52/RelB at the skp2 gene promoter to regulate G1- to S-phase progression. Embo J, 2006. 25(16): p. 3801-12.
63.Matushansky, I., F. Radparvar, and A.I. Skoultchi, Manipulating the onset of cell cycle withdrawal in differentiated erythroid cells with cyclin-dependent kinases and inhibitors. Blood, 2000. 96(8): p. 2755-64.
64.Blain, S.W. and J. Massague, Breast cancer banishes p27 from nucleus. Nat Med, 2002. 8(10): p. 1076-8.
65.el-Deiry, W.S., et al., WAF1, a potential mediator of p53 tumor suppression. Cell, 1993. 75(4): p. 817-25.
66.Rose, S.L., et al., p21 expression predicts outcome in p53-null ovarian carcinoma. Clin Cancer Res, 2003. 9(3): p. 1028-32.
67.Sohn, D., et al., p21 blocks irradiation-induced apoptosis downstream of mitochondria by inhibition of cyclin-dependent kinase-mediated caspase-9 activation. Cancer Res, 2006. 66(23): p. 11254-62.
68.Zhang, Y., N. Fujita, and T. Tsuruo, p21Waf1/Cip1 acts in synergy with bcl-2 to confer multidrug resistance in a camptothecin-selected human lung-cancer cell line. Int J Cancer, 1999. 83(6): p. 790-7.
69.Sonoda, H., et al., Significance of skp2 expression in primary breast cancer. Clin Cancer Res, 2006. 12(4): p. 1215-20.
70.van Duijn, P.W. and J. Trapman, PI3K/Akt signaling regulates p27(kip1) expression via Skp2 in PC3 and DU145 prostate cancer cells, but is not a major factor in p27(kip1) regulation in LNCaP and PC346 cells. Prostate, 2006. 66(7): p. 749-60.
71.Kastan, M.B. and J. Bartek, Cell-cycle checkpoints and cancer. Nature, 2004. 432(7015): p. 316-23.
72.Kawabe, T., G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther, 2004. 3(4): p. 513-9.
73.Shapiro, G.I. and J.W. Harper, Anticancer drug targets: cell cycle and checkpoint control. J Clin Invest, 1999. 104(12): p. 1645-53.
74.Dash, B.C. and W.S. El-Deiry, Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity. Mol Cell Biol, 2005. 25(8): p. 3364-87.
75.Lupu, R. and J.A. Menendez, Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators? Endocrinology, 2006. 147(9): p. 4056-66.
76.Deshpande, A., P. Sicinski, and P.W. Hinds, Cyclins and cdks in development and cancer: a perspective. Oncogene, 2005. 24(17): p. 2909-15.
77.Peters, G., The D-type cyclins and their role in tumorigenesis. J Cell Sci Suppl, 1994. 18: p. 89-96.
78.Nakayama, K.I., S. Hatakeyama, and K. Nakayama, Regulation of the cell cycle at the G1-S transition by proteolysis of cyclin E and p27Kip1. Biochem Biophys Res Commun, 2001. 282(4): p. 853-60.
79.Tsvetkov, L.M., et al., p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol, 1999. 9(12): p. 661-4.
80.Salucci, M., et al., Flavonoids uptake and their effect on cell cycle of human colon adenocarcinoma cells (Caco2). Br J Cancer, 2002. 86(10): p. 1645-51.
81.Puig, T., R. Porta, and R. Colomer, Fatty acid synthase: a new anti-tumor target]. Med Clin (Barc), 2009. 132(9): p. 359-63.
82.Wang, K.F. and B. Wu, Fatty acid synthase and prostate cancer. Zhonghua Nan Ke Xue, 2008. 14(8): p. 740-2.




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