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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 胡孟君(Meng-Chun Hu) | |
dc.contributor.author | Yi-Hsuan Kuo | en |
dc.contributor.author | 郭怡萱 | zh_TW |
dc.date.accessioned | 2021-06-08T02:48:47Z | - |
dc.date.copyright | 2017-09-08 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-08-18 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20440 | - |
dc.description.abstract | 癌症已是全球主要死因之一,乳癌為大部分國家女性最常被診斷出之癌症,在台灣乳癌已為女性癌症發生率之首十多年,雖然在早期治療的治癒率很高,但一旦產生轉移時,其死亡率會大幅提升。5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) 一開始發現其能抑制RNA合成,其主要機制是透過抑制cyclin-dependent kinase 9 (CDK9),避免CDK9組成之複合物positive transcription elongation factor (P-TEFb) 磷酸化RNA polymerase II的羧基末端區域,使得轉錄作用無法進入延長期。而之後有研究發現DRB可以造成大腸癌與白血病細胞產生細胞凋亡,具有做為癌症治療藥物之潛能。本篇主要探討DRB是否也可以促進乳癌細胞死亡,應用在乳癌治療。
透過細胞存活率分析 (MTT assay) 發現DRB處理後會造成乳癌細胞MCF7死亡。利用西方墨點法,發現DRB會引發細胞凋亡指標蛋白質cleaved PARP的表現,以及其上游活化態之cleaved caspase 9和caspase 7表現,因此說明DRB會誘發MCF7細胞凋亡。此外發現抑細胞凋亡蛋白Mcl-1在DRB處理後會快速減少,利用暫時性轉染法增加Mc1-1的表現,會降低cleaved PARP的量;利用shRNA lentivirus減少Mcl-1,則會增加cleaved PARP的量,顯示Mcl-1可能在DRB引發MCF7細胞凋亡扮演重要角色。以cleaved PARP做為細胞凋亡指標,我們發現PI3K抑制劑LY294002、pIκB抑制劑Bay117082以及1 μM MG132會加劇DRB誘發之細胞凋亡。其中以1 μM MG132之效應最為明顯,並且其活化態之cleaved caspase 9和caspase 7的量也有明顯增強。 本論文發現DRB引誘MCF7乳癌細胞凋亡,而Mcl-1可能扮演重要角色,此外1 μM MG132、LY294002與Bay117082可以加劇DRB引發的細胞凋亡,其中以低劑量的MG132效應最明顯,為未來DRB作為乳癌治療提供了更多可能性。 | zh_TW |
dc.description.abstract | Cancer is a leading cause of death worldwide. Breast cancer is the most commonly diagnosed cancer in females in most countries. In Taiwan, breast cancer has been the most frequently diagnosed for more than a decade. Although breast cancer is often curable when it is treated in early stage, metastatic disease dramatically increase the mortality rate. 5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) has been used as an inhibitor of RNA synthesis by blocking cyclin-dependent kinase 9 (CDK9). CDK9 is a component of P-TEFb complex, which phosphorylates the C-terminal domain of RNA polymerase II and promotes transcriptional elongation. DRB has been reported to trigger apoptosis in human colon carcinoma cells and leukemic cells. In this study, we investigate the potency of DRB to be chemotherapeutic target for breast cancer.
MTT assay showed that DRB treatment led to cell death in MCF7 breast cancer cells. Western blot data revealed that DRB induced the expression of apoptotic proteins, including cleaved PARP, caspase 9 and caspase 7 cleavage indicating that DRB trigger apoptosis in MCF7. DRB trigger apoptosis in MCF7. Treatment of MCF7 cells with DRB results in rapid decline in the levels of anti-apoptotic Mcl-1 protein. Overexpression of Mcl-1 increased the DRB-induced cleaved PARP. Knocked down Mcl-1 by shRNA lentivirus reduced cleaved PARP levels by DRB. These data suggest that Mcl-1 may play an important role in DRB-induce apoptosis. Furthermore, we found that the DRB-induced expression of cleaved PARP was enhanced in the presence of LY294002 (PI3K inhibitor), Bay117082 (pIκB inhibitor) and 1μM MG132. MG132 had the most dramatic effect to promote the expression of cleaved PARP, caspase 9 and caspase 7. Together, our results suggest Mcl-1 downregulation may be critical for apoptosis induced by DRB in MCF7 cells. MG132 potently sensitized MCF7 cells to DRB, which could be a potential therapeutic strategy for breast cancer. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:48:47Z (GMT). No. of bitstreams: 1 ntu-106-R04441014-1.pdf: 1963554 bytes, checksum: 5264e9edd10e0446f70454ce5679de34 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 致謝 I
目錄 II 表次 III 圖次 III 中文摘要 IV Abstract V 第一章 序論 1 一、乳癌簡介 1 二、DRB簡介 1 三、細胞凋亡簡介 2 四、Bcl-2家族簡介 4 五、NF-κB路徑簡介 4 六、研究目的 6 第二章 材料與方法 7 一、細胞培養 7 二、質體 7 三、藥品 7 四、核質分離 (cytosolic and nuclear proteins fraction) 8 五、西方墨點法 (Western blot) 分析 9 六、細胞存活率分析 (MTT assay) 11 七、暫時性轉染法 (Transient transfection) 11 八、shRNA knockdown 11 第三章 結果 13 一、DRB對MCF7細胞生長的影響 13 二、DRB引發 MCF7 細胞凋亡 13 三、MCF7細胞中,DRB對Bcl-2和p53家族蛋白質的影響 13 四、MCF7細胞中,增加與減少Mcl-1對DRB誘發的細胞凋亡之影響 14 五、MCF7細胞中DRB對Erk與Akt的影響 14 六、LY294002促進DRB誘發MCF7細胞凋亡 15 七、NF-κB對DRB誘發MCF7細胞凋亡之影響 15 八、MG132促進DRB誘發MCF7細胞凋亡 16 第四章 討論 18 一、Mcl-1在DRB引發之細胞凋亡與癌症中的重要性 18 二、MG132和PI3K加劇DRB誘發細胞凋亡的可能機制 19 三、DRB促進NF-κB進入細胞核之原因 20 參考文獻 22 | |
dc.language.iso | zh-TW | |
dc.title | "5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole誘發MCF7人類乳癌細胞凋亡" | zh_TW |
dc.title | 5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole induces apoptosis in MCF7 human breast cancer cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 張淑芬(Shwu-Fe Chang),徐立中(Li-Chung Hsu),余佳慧(Chia-Hui Yu) | |
dc.subject.keyword | DRB,細胞凋亡,人類乳癌, | zh_TW |
dc.subject.keyword | DRB,breast cancer,apoptosis, | en |
dc.relation.page | 42 | |
dc.identifier.doi | 10.6342/NTU201703858 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2017-08-18 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
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