(3.236.222.124) 您好!臺灣時間:2021/05/10 16:37
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

: 
twitterline
研究生:呂曜呈
研究生(外文):Yao-Cheng Lu
論文名稱:內質網依賴之鈣離子所介導之細胞質ROS為沒食子酸處理的人類口腔癌細胞中粒線體凋亡訊號與ATM-JNK訊息路徑的誘導者
論文名稱(外文):ER-Dependent Ca++-Mediated Cytosolic ROS as an Effector for Induction of Mitochondrial Apoptotic and ATM-JNK Signal Pathways in Gallic Acid-treated Human Oral Cancer Cells
指導教授:蘇鴻麟蘇鴻麟引用關係陳世順
指導教授(外文):Hong-Lin SuShih-Shun Chen
口試委員:林孟亮許游章鍾景光
口試委員(外文):Meng-Liang LinYou-Cheng HseuJing-Gung Chung
口試日期:2016-05-13
學位類別:博士
校院名稱:國立中興大學
系所名稱:生命科學系所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:45
中文關鍵詞:沒食子酸細胞凋亡內質網鈣離子ROSATMJNKGallic acid
外文關鍵詞:Gallic acidERCa++ROSATMJNKapoptosishuman oral cancer
相關次數:
  • 被引用被引用:0
  • 點閱點閱:185
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:44
  • 收藏至我的研究室書目清單書目收藏:0
目前研究指出,鈣離子從內質網(endoplasmic reticulum,ER)的釋放可能與氧化壓力所誘導的細胞凋亡(apoptosis)有關。利用內質網的鈣離子釋放抑制劑丹曲林(dantrolene)以及粒線體鈣離子吸收抑制劑Ru-360,本研究證明鈣離子從內質網的釋放與沒食子酸(gallic acid,GA)誘導人類口腔癌(human oral cancer,OC)細胞的活性氧化物(reactive oxygen species,ROS)的產生、粒線體膜電位的減少(ΔΨm)以及DNA片段化有關聯。而小干擾RNA(small interfering RNA)介導的蛋白質激酶RNA相似之內質網激酶降低則抑制了衣黴素(tunicamycin)引起之葡萄糖調控蛋白質78(78 kDa glucose-regulated protein)與C/EBP同源蛋白質(C/EBP homologous protein)的誘導、前半胱氨酸蛋白酶12(pro-caspase-12)的分裂,細胞質中鈣離子的增加與DAN片段化,但不會減低由GA所誘導的細胞質中鈣離子增加與細胞凋亡現象。GA所誘導共濟失調微血管擴張症候群變異基因(Ataxia telangiectasia mutated,ATM)介導之c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)磷酸化與細胞凋亡現象會被dantrolene所阻斷。利用ROS清除劑N-乙醯基半胱氨酸(N-acetylcysteine)可以確定ROS介導之ATM-JNK活化的專一性。而藉由專一性抑制劑KU55933、短髮夾狀RNA(short hairpin RNA)或是過度表現激酶活性喪失的ATM以阻斷ATM的表現則抑制了JNK的磷酸化,但無法完全地抑制由GA誘導的細胞質中ROS的產生、粒線體細胞色素c(cytochrome c)的釋放、前半胱氨酸蛋白酶3(pro-caspase-3)的分裂以及apoptosis。綜合以上,這些結果指出GA可能經由內質網的鈣離子介導之ROS產生以致粒線體細胞凋亡訊息路徑及ATM-JNK訊息路徑的活化來誘導人類口腔癌細胞SCC-4凋亡現象。

Release of calcium (Ca++) from the endoplasmic reticulum (ER) has been proposed to be involved in induction of apoptosis by oxidative stress. Using inhibitor of ER Ca++ release dantrolene and inhibitor of mitochondrial Ca++ uptake Ru-360, we demonstrated here that Ca++ release from the ER was associated with generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, and apoptosis of human oral cancer (OC) cells induced by gallic acid (GA). Small interfering RNA-mediated suppression of protein kinase RNA-like endoplasmic reticulum kinase inhibited tunicamycin-induced induction of 78 kDa glucose-regulated protein, C/EBP homologous protein, pro-caspase-12 cleavage, cytosolic Ca++ increase and apoptosis, but did not attenuate the increase in cytosolic Ca++ level and apoptosis induced by GA. Ataxia telangiectasia mutated (ATM)-mediated c-Jun N-terminal kinase (JNK) phosphorylation and apoptosis by GA was blocked by dantrolene. The specificity of ROS-mediated ATM-JNK activation was confirmed by the treatment with N-acetylcysteine, an ROS scavenger. Blockade of ATM activation by specific inhibitor KU55933, short hairpin RNA, or kinase-dead ATM overexpression suppressed JNK phosphorylation but did not completely inhibit cytosolic ROS production, mitochondrial cytochrome c release, pro-caspase-3 cleavage, and apoptosis induced by GA. When taken together, these results indicate that GA induces OC cell apoptosis by inducing the activation of mitochondrial apoptotic and ATM-JNK signal pathways, likely through ER Ca++-mediated ROS production.

中文摘要…………………………………………………………………………… i
英文摘要…………………………………………………………………………… ii
前言………………………………………………………………………………… 1
材料與方法………………………………………………………………………… 2
結果………………………………………………………………………………… 6
結論………………………………………………………………………………… 8
討論………………………………………………………………………………… 9
圖表………………………………………………………………………………… 11
參考文獻…………………………………………………………………………… 17
附錄………………………………………………………………………………… 21
Gallic acid化學性質……………………………………………………… 21
Gallic acid對人類癌細胞與正常細胞的存活度影響………………… 22
Gallic acid誘導老鼠細胞凋亡路徑圖…………………………………… 23
ATM的代謝訊息………………………………………………………… 24
鈣離子與細胞色素c在細胞凋亡的角色……………………………… 25
內質網壓力相關的訊息傳導…………………………………………… 26
鈣離子通道簡介圖……………………………………………………… 27
ATM與癌細胞化學抗性之關聯………………………………………… 28
ATM蛋白質功能區域…………………………………………………… 29
Gallic acid誘導BAX表現……………………………………………… 30
Ryanodine receptor簡介………………………………………………… 31
本研究所用抑制劑之基本介紹………………………………………… 32
期刊論文………………………………………………………………… 37


1.Abdelwahed, A., I. Bouhlel, I. Skandrani, K. Valenti, M. Kadri, P. Guiraud, R. Steiman, A. M. Mariotte, K. Ghedira, F. Laporte, M. G. Dijoux-Franca, and L. Chekir-Ghedira. 2007. Study of antimutagenic and antioxidant activities of gallic acid and 1,2,3,4,6-pentagalloylglucose from Pistacia lentiscus. Confirmation by microarray expression profiling. Chemico-biological interactions 165:1-13.
2.Agarwal, C., A. Tyagi, and R. Agarwal. 2006. Gallic acid causes inactivating phosphorylation of cdc25A/cdc25C-cdc2 via ATM-Chk2 activation, leading to cell cycle arrest, and induces apoptosis in human prostate carcinoma DU145 cells. Molecular cancer therapeutics 5:3294-3302.
3.Chen, C. Y., K. C. Chen, T. Y. Yang, H. C. Liu, and S. L. Hsu. 2013. Gallic Acid Induces a Reactive Oxygen Species-Provoked c-Jun NH2-Terminal Kinase-Dependent Apoptosis in Lung Fibroblasts. Evidence-based complementary and alternative medicine : eCAM 2013:613950.
4.Daneshfar, A., H. S. Ghaziaskar, and N. Homayoun. 2008. Solubility of Gallic Acid in Methanol, Ethanol, Water, and Ethyl Acetate. Journal of Chemical & Engineering Data 53:776-778.
5.Deniaud, A., O. Sharaf el dein, E. Maillier, D. Poncet, G. Kroemer, C. Lemaire, and C. Brenner. 2008. Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene 27:285-299.
6.Guo, Z., R. Deshpande, and T. T. Paull. 2010. ATM activation in the presence of oxidative stress. Cell cycle 9:4805-4811.
7.Guo, Z., S. Kozlov, M. F. Lavin, M. D. Person, and T. T. Paull. 2010. ATM activation by oxidative stress. Science 330:517-521.
8.He, Y., Q. Chen, and B. Li. 2008. ATM in oral carcinogenesis: association with clinicopathological features. Journal of cancer research and clinical oncology 134:1013-1020.
9.Heinonen, I. M., A. S. Meyer, and E. N. Frankel. 1998. Antioxidant activity of berry phenolics on human low-density lipoprotein and liposome oxidation. J Agr Food Chem 46:4107-4112.
10.Inoue, M., R. Suzuki, N. Sakaguchi, Z. Li, T. Takeda, Y. Ogihara, B. Y. Jiang, and Y. Chen. 1995. Selective induction of cell death in cancer cells by gallic acid. Biological & pharmaceutical bulletin 18:1526-1530.
11.Kim, Y. J. 2007. Antimelanogenic and antioxidant properties of gallic acid. Biological & pharmaceutical bulletin 30:1052-1055.
12.Kroemer, G., L. Galluzzi, and C. Brenner. 2007. Mitochondrial membrane permeabilization in cell death. Physiological reviews 87:99-163.
13.Lai, E., T. Teodoro, and A. Volchuk. 2007. Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology 22:193-201.
14.Lanner, J. T., D. K. Georgiou, A. D. Joshi, and S. L. Hamilton. 2010. Ryanodine receptors: structure, expression, molecular details, and function in calcium release. Cold Spring Harbor perspectives in biology 2:a003996.
15.Lin, M. L., S. S. Chen, R. Y. Huang, Y. C. Lu, Y. R. Liao, M. V. Reddy, C. C. Lee, and T. S. Wu. 2014. Suppression of PI3K/Akt signaling by synthetic bichalcone analog TSWU-CD4 induces ER stress- and Bax/Bak-mediated apoptosis of cancer cells. Apoptosis : an international journal on programmed cell death 19:1637-1653.
16.Lin, M. L., Y. C. Lu, J. G. Chung, Y. C. Li, S. G. Wang, G. S. N, C. Y. Wu, H. L. Su, and S. S. Chen. 2010. Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway. Cancer letters 291:46-58.
17.Lin, M. L., Y. C. Lu, J. G. Chung, S. G. Wang, H. T. Lin, S. E. Kang, C. H. Tang, J. L. Ko, and S. S. Chen. 2010. Down-regulation of MMP-2 through the p38 MAPK-NF-kappaB-dependent pathway by aloe-emodin leads to inhibition of nasopharyngeal carcinoma cell invasion. Molecular carcinogenesis 49:783-797.
18.Lin, M. L., Y. C. Lu, H. L. Su, H. T. Lin, C. C. Lee, S. E. Kang, T. C. Lai, J. G. Chung, and S. S. Chen. 2011. Destabilization of CARP mRNAs by aloe-emodin contributes to caspase-8-mediated p53-independent apoptosis of human carcinoma cells. Journal of cellular biochemistry 112:1176-1191.
19.Meek, D. W. 2009. Tumour suppression by p53: a role for the DNA damage response? Nature reviews. Cancer 9:714-723.
20.Mohanty, S., S. Saha, S. H. D. Md, A. Adhikary, S. Mukherjee, A. Manna, S. Chakraborty, M. Mazumdar, P. Ray, K. Das, J. Chakraborty, G. Sa, and T. Das. 2014. ROS-PIASgamma cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant tumors. Cell death & disease 5:e1021.
21.Nutt, L. K., J. Chandra, A. Pataer, B. Fang, J. A. Roth, S. G. Swisher, R. G. O''Neil, and D. J. McConkey. 2002. Bax-mediated Ca2+ mobilization promotes cytochrome c release during apoptosis. The Journal of biological chemistry 277:20301-20308.
22.Nutt, L. K., A. Pataer, J. Pahler, B. Fang, J. Roth, D. J. McConkey, and S. G. Swisher. 2002. Bax and Bak promote apoptosis by modulating endoplasmic reticular and mitochondrial Ca2+ stores. The Journal of biological chemistry 277:9219-9225.
23.Ozcelik, B., M. Kartal, and I. Orhan. 2011. Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids. Pharmaceutical biology 49:396-402.
24.Pinton, P., D. Ferrari, E. Rapizzi, F. Di Virgilio, T. Pozzan, and R. Rizzuto. 2002. A role for calcium in Bcl-2 action? Biochimie 84:195-201.
25.Pinton, P., C. Giorgi, R. Siviero, E. Zecchini, and R. Rizzuto. 2008. Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene 27:6407-6418.
26.Rizzuto, R., and T. Pozzan. 2006. Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiological reviews 86:369-408.
27.Shi, J., J. Yu, J. E. Pohorly, and Y. Kakuda. 2003. Polyphenolics in grape seeds-biochemistry and functionality. Journal of medicinal food 6:291-299.
28.Shiloh, Y. 2003. ATM and related protein kinases: safeguarding genome integrity. Nature reviews. Cancer 3:155-168.
29.Sullivan, K. D., V. V. Palaniappan, and J. M. Espinosa. 2015. ATM regulates cell fate choice upon p53 activation by modulating mitochondrial turnover and ROS levels. Cell cycle 14:56-63.
30.Thomenius, M. J., and C. W. Distelhorst. 2003. Bcl-2 on the endoplasmic reticulum: protecting the mitochondria from a distance. Journal of cell science 116:4493-4499.
31.Thomenius, M. J., N. S. Wang, E. Z. Reineks, Z. Wang, and C. W. Distelhorst. 2003. Bcl-2 on the endoplasmic reticulum regulates Bax activity by binding to BH3-only proteins. The Journal of biological chemistry 278:6243-6250.
32.Wang, L., A. J. Mosel, G. G. Oakley, and A. Peng. 2012. Deficient DNA damage signaling leads to chemoresistance to cisplatin in oral cancer. Molecular cancer therapeutics 11:2401-2409.
33.Wang, Y., X. Huang, H. Cang, F. Gao, T. Yamamoto, T. Osaki, and J. Yi. 2007. The endogenous reactive oxygen species promote NF-kappaB activation by targeting on activation of NF-kappaB-inducing kinase in oral squamous carcinoma cells. Free radical research 41:963-971.
34.Weng, S. W., S. C. Hsu, H. C. Liu, B. C. Ji, J. C. Lien, F. S. Yu, K. C. Liu, K. C. Lai, J. P. Lin, and J. G. Chung. 2015. Gallic acid induces DNA damage and inhibits DNA repair-associated protein expression in human oral cancer SCC-4 cells. Anticancer research 35:2077-2084.
35.Yang, Z. S., D. P. Zhang, H. Y. Long, and Y. C. Liu. 2008. Electrochemical behavior of gallic acid interaction with DNA and detection of damage to DNA. Journal of Electroanalytical Chemistry 624:91-96.
36.Yeh, R. D., J. C. Chen, T. Y. Lai, J. S. Yang, C. S. Yu, J. H. Chiang, C. C. Lu, S. T. Yang, C. C. Yu, S. J. Chang, H. Y. Lin, and J. G. Chung. 2011. Gallic acid induces G(0)/G(1) phase arrest and apoptosis in human leukemia HL-60 cells through inhibiting cyclin D and E, and activating mitochondria-dependent pathway. Anticancer research 31:2821-2832.
37.Yoshioka, K., T. Kataoka, T. Hayashi, M. Hasegawa, Y. Ishi, and H. Hibasami. 2000. Induction of apoptosis by gallic acid in human stomach cancer KATO III and colon adenocarcinoma COLO 205 cell lines. Oncology reports 7:1221-1223.
38.Zong, W. X., C. Li, G. Hatzivassiliou, T. Lindsten, Q. C. Yu, J. Yuan, and C. B. Thompson. 2003. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. The Journal of cell biology 162:59-69.
39.Zuo, Y., H. Chen, and Y. Deng. 2002. Simultaneous determination of catechins, caffeine and gallic acids in green, Oolong, black and pu-erh teas using HPLC with a photodiode array detector. Talanta 57:307-316.


QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
系統版面圖檔 系統版面圖檔