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系統識別號 U0026-1301201413540300
論文名稱(中文) 探討S6K1抑制劑對HEL細胞的影響
論文名稱(英文) The effect of S6K1 inhibitor on HEL cells
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 102
學期 1
出版年 103
研究生(中文) 劉翊亭
研究生(英文) I-Ting Liu
學號 S26001012
學位類別 碩士
語文別 中文
論文頁數 101頁
口試委員 指導教授-簡偉明
口試委員-陳清玉
口試委員-錢偉鈞
中文關鍵字 急性骨髓性白血病  PI3K抑制劑  mTOR  S6K抑制劑 
英文關鍵字 acute myeloid leukemia  PI3K inhibitor  mTOR  S6K1 inhibitor 
學科別分類
中文摘要 急性骨髓性白血病是成人最常見的白血病,而且全世界每年有超過二十五萬的成年人被診斷罹患此疾病,過去文獻都指出急性骨髓性白血病病患的血癌細胞中PI3K/AKT/mTOR訊息傳遞路徑有持續活化的情形,並且此路徑對於血癌細胞的增生(proliferation)、存活(survival)以及耐藥性(drug resistance)非常地重要,而 S6K1是mTOR最重要的下游蛋白之一,過去已知S6K1對於生物體的生長和發育扮演著重要的角色,直到近幾年S6K1才被發現與癌症有相關,目前已知在乳癌、大腸癌、肺癌、卵巢癌細胞中S6K1都有過度表達的情形,此現象也和造成病人預後較差有關連。但是直到目前為止S6K1在急性骨髓性白血病中所扮演的角色尚未清楚了解。因此本實驗主要是想探討,S6K1有沒有在HEL細胞扮演增生或是存活的角色;以及S6K1會不會影響化療藥物對HEL細胞的毒性。首先,我們先利用alamar blue assay來觀察S6K1的抑制劑DG2對HEL細胞增生能力的影響,實驗發現給予DG2之後細胞的增生速率隨之下降,若先給予DG2再以化療藥物Cisplatin和Etoposide來抑制細胞增生,發現DG2會增加Cisplatin和Etoposide抑制HEL細胞增生的效果。接著又利用流氏細胞儀分析DG2對HEL細胞死亡率的影響,結果顯示給予DG2會些微增加細胞的死亡率,若先給予DG2再以化療藥物Cisplatin和Etoposide來促進細胞死亡,發現DG2會增加Cisplatin和Etoposide促進HEL細胞死亡的效果。另外想了解DG2是否藉由細胞凋亡來促進細胞死亡,以西方墨點法分析發現不論是單獨給DG2或先給予DG2再給化療藥物皆不影響PARP cleaved表現量。最後想了解S6K1上游的PI3K 對HEL細胞增生的影響,實驗發現PI3K的抑制劑ZSTK474會顯著的抑制HEL細胞增生,若先給予ZSTK474再給化療藥物,發現ZSTK474會明顯增加Cisplatin和Etoposide抑制HEL細胞增生的效果。綜合以上實驗結果可知DG2能抑制HEL細胞增生以及些微增加HEL細胞死亡,但其抑制細胞增生的效果卻沒有ZSTK474來的好,在此S6K1提供了一個治療急性骨髓性白血病的新方向,但未來還需更多實驗來進一步了解S6K1在急性骨髓性白血病中所扮演的角色。
英文摘要 Acute myeloid leukemia (AML) is a general boold disease in adults, there are over two hundred and fifty thousand of adults were diagnosed with AML over the world each year. Studies have revealed that PI3K/AKT/mTOR pathway continued to be activated in the AML cells. PI3K/AKT/mTOR pathway is very important for the proliferation, survival rate and drug resistance of acute leukemia cells. Recently, scientists created several small molecular inhibitors for PI3K/AKT/mTOR pathway, but the most results seem useless for AML treatment. S6K1 is one of the important proteins of mTOR downstream. It has been known S6K1 plays a critical role of growth and development in the organism. Untill recent years, S6K1 was found that involves with cancer. Currently, the data shows S6K1 overexpression of breast cancer, colorectal cancer, lung cancer and ovarian cancer that relative with the prognosis of patients. However, the role of S6K1 in AML cells is still unclear. This study not only explored the effect of cell proliferation and survival rate of S6K1, but also S6K1 that whether affect the cytotoxicity by treating chemotherapeutic drugs.The first, we observed the effect of the proliferation of HEL cells by treated S6K1 inhibitor, DG2. The data shows DG2 decreased the proliferation of HEL cells and it also has the synergistic ability to inhibit HEL cell proliferation by treated with chemotherapeutic drugs such as Cisplatin and Etoposide. There is few mortality in HEL cells with DG2, but the results from analysis of flow cytometer reveals the mortality was increased by added chemotherapeutic drugs included Cisplatin and Etoposidthe after treated with DG2. In addition, DG2 whether promote the death of HEL cells through apoptosis is we want to understand. We tested the apoptosis by using western blott analysis. The data shows either treated with DG2 alone or DG2 and chemotherapeutic drugs that could not affect PARP cleaved expression. Finally, we want to understand the influence of S6K1 upstream, PI3K, in the HEL cell proliferation. The results reveal that the inhibitor of PI3K, ZSTK474, inhibited the proliferation of HEL cells significantly. Another way, the inhibition of HEL cell proliferation was increased with Cisplatin and Etoposide significantly by pre-treated with ZSTK474. Combined above, DG2 not only inhibited the proliferation but also increased few mortality in HEL cells. However, the efficiency of DG2 for the proliferation is less than PI3K inhibitor, ZSTK474, in HEL cells. Here, we provide a novel direction for AML treatment. In order to understand the role of S6K1 in AML that needs more experiments further.
論文目次 封面..............................................Ⅰ
口試合格證明.......................................Ⅱ
摘要..............................................Ⅲ
Abstract.........................................Ⅴ
誌謝..............................................Ⅶ
目錄..............................................Ⅷ
縮寫表............................................Ⅸ

緒論...............................................1
材料與方法.........................................20
實驗結果...........................................39
討論...............................................49
結論...............................................54
參考文獻............................................55
附錄................................................77
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