岩藻糖基转移酶IV及PKCα的表达抑制诱导A431细胞凋亡作用的研究
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摘要
α1,3-岩藻糖基转移酶(α1,3 FUT)参与Lewis糖链合成最后一步岩藻糖化反应,包括FUT3、FUT4、FUT5、FUT6、FUT7、FUT9六种。其中FUT4是催化LeY寡糖合成的关键酶,它可将GDP-岩藻糖转移到N-乙酰氨基葡萄糖(GlcNAc)的末端形成α1,3糖苷键。正常生理条件下,FUT4主要在白细胞和上皮细胞中表达;而在肠癌、克隆癌、胰腺癌中表达异常升高。因此,调控特异岩藻糖基转移酶表达可改变LeY寡糖的合成,进而影响LeY寡糖参与的生物学功能。
LeY寡糖[Fucα1→2Galβ1→4(Fucα1→3)GlcNAcβ1→R]是细胞表面的糖蛋白和糖脂分子上的Ⅱ型岩藻化寡糖。研究显示:LeY寡糖参与个体发育、器官形成、造血细胞分化及肿瘤发生与转移等。约70-90%的人类上皮细胞来源的肿瘤高表达LeY,并与肿瘤细胞的增殖、浸润和转移潜能密切相关,因此被认为是一种肿瘤相关的标志物。
本课题组前期工作表明:应用RNAi技术抑制FUT4表达及利用LeY寡糖抗原的特异抗体封闭LeY,可抑制人上皮癌细胞A431的生长;而FUT4的过表达可促进LeY的合成,并抑制细胞凋亡。关于FUT4对人上皮癌细胞增殖和凋亡的影响机制还不完全清楚。信号传导分子蛋白激酶C在肿瘤的发生发展中有重要作用,并且蛋白激酶Cα亚型(PKCα)作为靶向药物治疗肿瘤已经在临床上得到初步应用。
本文旨在通过细胞凋亡相关检测及Western blot等方法,研究转染FUT4干扰序列和反义PKCα对A431细胞凋亡作用的影响及初步探讨其作用机制。实验结果表明:FUT4 RNAi及PKCαAS均可以可以诱导A431细胞的凋亡,而且二者有一定的协同作用;FUT4 RNAi可能通过调控PKCα的表达诱导细胞凋亡。
α1,3-fucosyltransferases(α1,3 FUT)participate in the fucosylation synthesis of Lewis oligosaccharide chains by transferring GDP-fucose to the terminal N-acetyllactosamine(GlcNAc)with theα1,3 orα1,4 linkage.α1,3 FUTs include FUT3, 4, 5, 6, 7 and 9 genes. Fucosyltransferase IV (FUT4) is an essential enzyme that catalyzes the synthesis of Lewis Y (LeY) by transferring GDP-fucose to the terminal N-acetylglucosamine(GlcNAc)with theα1,3-linkage. FUT4 is mainly expressed in leukocyte and some epithelial cells. FUT4 was found abnormally expressed, eg, gastric carcinoma, colorectal cancerous, pancreatic cancer, et al. Therefore, regulating the expression of fucosyltransferases may change the synthesis of LeY and affect the biological function of LeY.
LeY antigen carried by the glycoproteins and glycolipids on cell surface, is a difucosylated oligosaccharide with the chemical structure [Fucα1→2Galβ1→4(Fucα1→3)GlcNAcβ1→R] . LeY is able to facilitate henogenesis, organ formation, cell differentiation, tumorigenesis et al. LeY has been recognized as a tumor-associated antigen in a variety of cancer process particularly in cell proliferation, invasion and metastasis, highly expressed LeY is found in the majority (70-90%) of human cancers of epithelial orogin.
The previous work in our lab showed that the suppression of FUT4 by RNAi and LeY antibody could inhibit the A431 cell proliferation, the overpression of FUT4 could increase the synthesis of LeY and inhibit cell apoptosis. The effect of FUT4 on cell proliferation and cell apoptosis in A431 cells is not clearly elucidated. It is found that protien kinase C has an important role in the development and progress of cancers. PKCαas a targeted anti-cancer drugs has made significant progress in clinic trial. This work mainly explored the effect of FUT4 RNAi and PKCαas on cell apoptosis in A431 cells.
LeY寡糖[Fucα1→2Galβ1→4(Fucα1→3)GlcNAcβ1→R]是细胞表面的糖蛋白和糖脂分子上的Ⅱ型岩藻化寡糖。研究显示:LeY寡糖参与个体发育、器官形成、造血细胞分化及肿瘤发生与转移等。约70-90%的人类上皮细胞来源的肿瘤高表达LeY,并与肿瘤细胞的增殖、浸润和转移潜能密切相关,因此被认为是一种肿瘤相关的标志物。
本课题组前期工作表明:应用RNAi技术抑制FUT4表达及利用LeY寡糖抗原的特异抗体封闭LeY,可抑制人上皮癌细胞A431的生长;而FUT4的过表达可促进LeY的合成,并抑制细胞凋亡。关于FUT4对人上皮癌细胞增殖和凋亡的影响机制还不完全清楚。信号传导分子蛋白激酶C在肿瘤的发生发展中有重要作用,并且蛋白激酶Cα亚型(PKCα)作为靶向药物治疗肿瘤已经在临床上得到初步应用。
本文旨在通过细胞凋亡相关检测及Western blot等方法,研究转染FUT4干扰序列和反义PKCα对A431细胞凋亡作用的影响及初步探讨其作用机制。实验结果表明:FUT4 RNAi及PKCαAS均可以可以诱导A431细胞的凋亡,而且二者有一定的协同作用;FUT4 RNAi可能通过调控PKCα的表达诱导细胞凋亡。
α1,3-fucosyltransferases(α1,3 FUT)participate in the fucosylation synthesis of Lewis oligosaccharide chains by transferring GDP-fucose to the terminal N-acetyllactosamine(GlcNAc)with theα1,3 orα1,4 linkage.α1,3 FUTs include FUT3, 4, 5, 6, 7 and 9 genes. Fucosyltransferase IV (FUT4) is an essential enzyme that catalyzes the synthesis of Lewis Y (LeY) by transferring GDP-fucose to the terminal N-acetylglucosamine(GlcNAc)with theα1,3-linkage. FUT4 is mainly expressed in leukocyte and some epithelial cells. FUT4 was found abnormally expressed, eg, gastric carcinoma, colorectal cancerous, pancreatic cancer, et al. Therefore, regulating the expression of fucosyltransferases may change the synthesis of LeY and affect the biological function of LeY.
LeY antigen carried by the glycoproteins and glycolipids on cell surface, is a difucosylated oligosaccharide with the chemical structure [Fucα1→2Galβ1→4(Fucα1→3)GlcNAcβ1→R] . LeY is able to facilitate henogenesis, organ formation, cell differentiation, tumorigenesis et al. LeY has been recognized as a tumor-associated antigen in a variety of cancer process particularly in cell proliferation, invasion and metastasis, highly expressed LeY is found in the majority (70-90%) of human cancers of epithelial orogin.
The previous work in our lab showed that the suppression of FUT4 by RNAi and LeY antibody could inhibit the A431 cell proliferation, the overpression of FUT4 could increase the synthesis of LeY and inhibit cell apoptosis. The effect of FUT4 on cell proliferation and cell apoptosis in A431 cells is not clearly elucidated. It is found that protien kinase C has an important role in the development and progress of cancers. PKCαas a targeted anti-cancer drugs has made significant progress in clinic trial. This work mainly explored the effect of FUT4 RNAi and PKCαas on cell apoptosis in A431 cells.
引文
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3. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992; 258:607-611.
4. Wang XY, Repasky E, Liu HT. Antisense inhibition of protein kinase Cαreverses the transformed phenotype in human lung carcinoma cells. Experimental Cell Research. 1999; 250: 253-263.
5. Ways DK, Kukoly CA, DeVente J, et al. MCF-7 breast cancer cells transfected with PKC-αexhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. The Journal of Clinical Investigation. 1995; 95: 190-215.
6. Mandil R, Ashenazi E, Blass M, et al.Protein kinase C-αand protein kinase C-δplay opposite roles in the proliferation and apoptosis of glioma cells. Cancer Research. 2001; 61:4612-4619.
7. Leli U, Parker PJ, Shea TB. Intracellular delivery of protein kinase C-alpha or -epsilon isoform-specific antibodies promotes acquisition of a morphologically differentiated phenotype in neuroblastoma cells. FEBS Letters.1992; 297: 91–94.
8. Ya-Ching H, Hsiao-Ching J, Rei-Cheng Y, et al.Suppression of protein kinase C-αtriggers apoptosis through down-regulation of BCL-xl in a rat hepatic epithelial cell line. Shock. 2003; 19:582-587.
9. Xiao-Hua J, Shui-Ping T, Jian-Tao C, et al. Antisense Targeting Protein Kinase Cαandβ1 Inhibits Gastric Carcinogenesis. Cancer research. 2004 August 15; 64: 5787-5794.
10. Liu B, Maher RJ, Hannun YA, Porter AT, Honn KV. 12(S)-HETE enhancement of prostate tumor cell invasion: selective role of PK C-α. Journal of the National Cancer Institute. 1994; 86: 1145–1151.
11. Ahmad S, Glazer RI. Expression of the antisense cDNA for protein kinase Calpha attenuates resistance in doxorubicin-resistant MCF-7 breast carcinoma cells. Molecular Pharmacology. 1993; 43: 858-862.
12. Jiang J, Chen X, Shen J, et al. Beta1,4-galactosyltransferase V functions as a positive growth regulator in glioma. The Journal of Biological Chemistry. 2006; 281: 9482-9489.
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17. Carter A. Protein kinase C as a drug target: implications for drug or diet prevention and treatment of cancer. Current Drug Targets. 2000; 1: 163-183.
18. Tu C, Chou K, Chen C ,et al. Protein kinase C-mediated tyrosine phosphorylation of paxillin and focal adhesion kinase requires cytoskeletal integrity and is uncoupled to mitogen-activated protein kinase activation in human hepatoma cells.Journal of Biomedical Science. 2001; 8 :184-190.
19. Hsieh YH,Wu TT,Tsai JH,et a1. PKC alpha expression regulated by Flk-l and MZF-1 in human HCC cells. Biochemical and Biophysical Research Commu- nications. 2006; 339: 2l7-225.
20. Leirdal M , Sioud M. Ribozyme inhibition of the protein kinase C alpha triggers apoptosis in glima cells. Journal of Cancer. l999; 80: l558-1564.
21.朱兴榴,黄骥,王燕燕.肺癌组织巾PKC-α蛋白的表达与肺癌临床病理特征的关系.肿瘤防治研究. 2005;32: 490-492.
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24.黄涛,冯延平,高军,等.蛋白激酶C-α反义寡核苷酸对人胰腺癌BXPC-3细胞体外侵袭力的影响.郑州大学学报(医学版) . 2006; 41: 892-894.
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3. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992; 258:607-611.
4. Wang XY, Repasky E, Liu HT. Antisense inhibition of protein kinase Cαreverses the transformed phenotype in human lung carcinoma cells. Experimental Cell Research. 1999; 250: 253-263.
5. Ways DK, Kukoly CA, DeVente J, et al. MCF-7 breast cancer cells transfected with PKC-αexhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. The Journal of Clinical Investigation. 1995; 95: 190-215.
6. Mandil R, Ashenazi E, Blass M, et al.Protein kinase C-αand protein kinase C-δplay opposite roles in the proliferation and apoptosis of glioma cells. Cancer Research. 2001; 61:4612-4619.
7. Leli U, Parker PJ, Shea TB. Intracellular delivery of protein kinase C-alpha or -epsilon isoform-specific antibodies promotes acquisition of a morphologically differentiated phenotype in neuroblastoma cells. FEBS Letters.1992; 297: 91–94.
8. Ya-Ching H, Hsiao-Ching J, Rei-Cheng Y, et al.Suppression of protein kinase C-αtriggers apoptosis through down-regulation of BCL-xl in a rat hepatic epithelial cell line. Shock. 2003; 19:582-587.
9. Xiao-Hua J, Shui-Ping T, Jian-Tao C, et al. Antisense Targeting Protein Kinase Cαandβ1 Inhibits Gastric Carcinogenesis. Cancer research. 2004 August 15; 64: 5787-5794.
10. Liu B, Maher RJ, Hannun YA, Porter AT, Honn KV. 12(S)-HETE enhancement of prostate tumor cell invasion: selective role of PK C-α. Journal of the National Cancer Institute. 1994; 86: 1145–1151.
11. Ahmad S, Glazer RI. Expression of the antisense cDNA for protein kinase Calpha attenuates resistance in doxorubicin-resistant MCF-7 breast carcinoma cells. Molecular Pharmacology. 1993; 43: 858-862.
12. Jiang J, Chen X, Shen J, et al. Beta1,4-galactosyltransferase V functions as a positive growth regulator in glioma. The Journal of Biological Chemistry. 2006; 281: 9482-9489.
13. Hellstrom I, Garrigues HJ, Garrigues U, et al. Highly tumor-reactive, internalizing, mouse monoclonal antibodies to Le(y)-related cell surface antigens. Cancer Research. 1990 Apr 1; 50:2183-2190.
14. Madjd Z, Parsons T, Watson NF, et al. Highexpression of Lewis y/b antigens is associated with decreased survival in lymphnode negative breast carcinomas. Breast Cancer Research. 2005; 7:R780-787.
15. Zhang Z, Sun P, Liu J, et al. Suppression of FUT1/FUT4 expression by siRNA inhibits tumor growth. Biochim Biophys Acta. 2008 Feb; 1783:287-296.
16. Idris I, Gray S, Donnelly R. Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes. Diabetologia. 2001; 44: 659-673.
17. Carter A. Protein kinase C as a drug target: implications for drug or diet prevention and treatment of cancer. Current Drug Targets. 2000; 1: 163-183.
18. Tu C, Chou K, Chen C ,et al. Protein kinase C-mediated tyrosine phosphorylation of paxillin and focal adhesion kinase requires cytoskeletal integrity and is uncoupled to mitogen-activated protein kinase activation in human hepatoma cells.Journal of Biomedical Science. 2001; 8 :184-190.
19. Hsieh YH,Wu TT,Tsai JH,et a1. PKC alpha expression regulated by Flk-l and MZF-1 in human HCC cells. Biochemical and Biophysical Research Commu- nications. 2006; 339: 2l7-225.
20. Leirdal M , Sioud M. Ribozyme inhibition of the protein kinase C alpha triggers apoptosis in glima cells. Journal of Cancer. l999; 80: l558-1564.
21.朱兴榴,黄骥,王燕燕.肺癌组织巾PKC-α蛋白的表达与肺癌临床病理特征的关系.肿瘤防治研究. 2005;32: 490-492.
22. Lahn M, Paterson BM, Sundell K, et al. The role of protein kinase C-alpha (PKC-α) in malignancies of the gastrointestinal tract. European Journal of Cancer. 2004, 40: 10-20.
23.吴孝杰,庞江琳,孙显斌. PKC-α反义核酸对子宫颈癌HeLa细胞增殖及c-myc、c-jun表达的影响.现代肿瘤学. 2004; 12: 291-293.
24.黄涛,冯延平,高军,等.蛋白激酶C-α反义寡核苷酸对人胰腺癌BXPC-3细胞体外侵袭力的影响.郑州大学学报(医学版) . 2006; 41: 892-894.
25. Mellor H, Parker PJ. The extended protein kinase C super family. Biochem Journal. 1998; 332: 281-292.
26.曹冬旭,石英,孔英,燕秋.着床期小鼠子宫内膜MAPK的表达及LeY寡糖对其表达的调控.生殖医学杂志. 2005; 14: 284-287.
27. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. The Journal of Clinical Oncology. 2002; 20: 1-13.
28. Arteaga C L. Overview of epidermal growth factor receptor biology andits roleas a therapeutic target in human neoplasia. Seminars in oncology.2002; 29: 3-9.
29. Klinger M, Farhan H, Just H, et al. Antibodies directed against Lewis-Y antigen inhibitsignaling of Lewis-Y modified ErbB receptors. Cancer Research. 2004; 64:1087-1093.
30. Farhan H, Schuster C, Klinger M, et al. Inhibition of xenograft tumor growth and downregulation of ErbB receptors by an antibody directed against Lewis-Y antigen. The Journal of Pharmacology and Experimental Thera- peutics.2006; 319; 1459-1466.
31. Lee F T, Mountain A J, Kelly M P, et al. Enhanced efficacy of radio- immunotherapy with 90Y-CHX-A''-DTPA-hu3S193 by inhibition of epidermal growth factor receptor (EGFR) signaling with EGFR tyrosine kinase inhibitor AG1478. 2005; 11:7080-7086.
32. Co M S, Baker J, Bednarik K, et al. Humanized anti-Lewis Y antibodies: in vitro properties and pharmacokinetics in rhesus monkeys. Cancer Research. 1996; 56: 1118-1125.
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