系統識別號 U0026-1407201210542700
論文名稱(中文) 探討砷化合物誘導MA-10小鼠萊氏腫瘤細胞凋亡之影響
論文名稱(英文) The Apoptotic Effect of Arsenic Compounds on MA-10 Mouse Leydig Tumor Cells
校院名稱 成功大學
系所名稱(中) 細胞生物及解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 100
學期 2
出版年 101
研究生(中文) 穆儀芬
研究生(英文) Yi-Fen Mu
學號 T96994016
學位類別 碩士
語文別 英文
論文頁數 73頁
口試委員 指導教授-黃步敏
中文關鍵字 亞砷酸鈉  二甲基砷酸  萊氏腫瘤細胞  硫胱氨酸蛋白酶  Bcl-2家族蛋白  有絲分裂活化蛋白質激酶訊息路徑  蛋白激酶B訊息路徑  活性氧化物 
英文關鍵字 Sodium arsenite  Dimethylarsenic acid  Leydig tumor cell  Caspase cascade  Bcl-2 family proteins  Reactive oxygen species (ROS)  MAPK pathway  Akt pathway 
中文摘要 砷是一種於大自然常見的環境毒物,研究顯示長期暴露之下會對人體造成毒害,嚴重者會造成神經病變、心血管疾病、糖尿病、高血壓…等,然而,近來有學者利用三氧化二砷(As2O3;俗稱砒霜)治療罹患急性前骨髓性白血病(Acute promyelocytic leukemia; APL)的病人,在臨床試驗上發現其病情能得到緩解。同時,在體外研究發現三氧化二砷會誘導不成熟的白血球細胞走向細胞凋亡。而根據統計,男性癌症中,睪丸癌發生率有逐年增加的趨勢,為提高患者的治療品質,因而希望能尋求更好的治療方針。由於過去研究證實砷的抗癌效用,因此進一步想探討砷是否對萊氏細胞腫瘤有相似的抗癌效果。我們利用MA-10細胞株(小鼠萊氏腫瘤細胞)處理不同濃度的亞砷酸鈉(Sodium arsenite, NaAsO2)及二甲基砷酸((CH3)2AsO2H, DMA)來探討其抗癌效用及其分子機制。研究發現在100 μM亞砷酸鈉作用三小時以及1 mM二甲基砷酸作用二十四小時以後,MA-10細胞出現許多典型細胞凋亡(apoptosis)的特徵,例如:細胞鼓起(cell rounded up)以及細胞膜發泡(membrane blebbing)等現象;此外,透過細胞存活率分析(MTT viability test)發現處理10 μM亞砷酸鈉細胞以及10 mM二甲基砷酸,都會造成細胞存活率顯著的下降(p<0.05);利用流式細胞儀分析,可觀察到subG1 以及G2/M期的顯著上升(p<0.05);透過細胞雙染試驗,更證實砷化合物(亞砷酸鈉及二甲基砷酸)確實會誘導MA-10細胞株走向凋亡。進一步,砷化合物也會促使硫胱氨酸蛋白酶(caspase-8, -9 and -3)的活化以及聚(腺苷二磷酸-核糖)多聚酶(PARP)的裂解;利用硫胱氨酸蛋白酶抑制劑(caspase inhibitor)會阻斷由砷化合物所誘導的硫胱氨酸蛋白酶(caspase-8, -9 and -3)活化。值得注意的是只有亞砷酸鈉會顯著增加Fas ligand(FasL)的蛋白質表現而非二甲基砷酸。另外,亞砷酸鈉和二甲基砷酸都會造成Bax移位(Bax translocation)、Bid的切截(Bid truncation)、cytochrome C的釋放(cytochrome C release)以及活性氧化物(reactive oxygen species, ROS)的增加。ERK1/2, JNK, p38 MAPK訊息傳遞路徑的活化也參與在砷化合物(亞砷酸鈉及二甲基砷酸)所誘導的細胞凋亡當中;然而,砷化合物(亞砷酸鈉及二甲基砷酸)會降低Akt的磷酸化並且也會影響Akt的蛋白質表現。根據以上的實驗結果發現砷化合物(亞砷酸鈉及二甲基砷酸)會使得MA-10細胞株活化外在死亡受體細胞凋亡路徑(extrinsic; death receptor pathway)以及內在粒腺體細胞凋亡路徑(intrinsic; mitochondrial pathway)以及改變MAPK和Akt訊息傳遞路徑的活性,而導致細胞凋亡。此外,實驗結果也發現亞砷酸鈉比二甲基砷酸在MA-10細胞株之中具有較高的療效。
英文摘要 Arsenic is an environmental toxicant. The research has shown that long term arsenic exposure can be harmful to human body, and has been associated with some chronic diseases. However, some researchers surprisingly found that arsenic trioxide showed the good therapeutic effect on acute promyelocytic leukemia (APL) patients, and in vitro studies indicated that arsenics could induce APL cell apoptosis. Because of increasing incident rate of the testicular cancer, we assumed whether arsenics might show the same apoptotic effect on testicular cancer cells. To test our hypothesis, we used MA-10 cells, a mouse Leydig tumor cell line, and treated with different concentrations of sodium arsenite and dimethylarsenic acid to determine the apoptotic effect and mechanism. Our data showed that MA-10 cells appeared rounded-up and exhibited membrane blebbings after treatment with 100 μM sodium arsenite for 3 h or 1 mM dimethylarsenic acid for 24 h. Besides, MTT viability test demonstrated that MA-10 cells appeared apoptotic after treatment with 10 μM sodium arsenite for 6 h or 10 mM dimethylarsenic acid for 24 h. In flow cytometry analysis, both sodium arsenite and dimethylarsenic acid significantly increased the ratio of subG1 and G2/M phases (p<0.05). Annexin V/PI double staining study further demonstrated that arsenic compounds did significantly induce MA-10 cell apoptosis (p<0.05). Moreover, the arsenic-induced cell apoptosis was accompanied by the upregulation of cleaved caspase-8, -9, -3 and PARP proteins, and the caspase inhibitor reversed caspase-8, -9 and -3 cleavages in MA-10 cells. Interesting, the expression of FasL could be upregulated by sodium arsenite but not dimethylarsenic acid. Besides, Bax translocation, Bid truncation, cytochrome C release and elevation of ROS generation were also involved in arsenic-induced cell apoptosis. Furthermore, the activation of ERK1/2, JNK, p38 MAPK pathway could be induced by both sodium arsenite and dimethylarsenic acid in MA-10 cells. In addition, arsenic compounds decreased the expression and phosphorylation of Akt protein. In conclusion, arsenic compounds could induce cell apoptosis in MA-10 cells through the activation of intrinsic and extrinsic caspase cascades and the modulation of MAPK and Akt pathways, and sodium arsenite had higher efficacy than dimethylarsenic acid.
Chinese abstract...........................................I
English abstract.........................................III
TABLE OF CONTENTS.........................................VI
LIST OF FIGURES.........................................VIII
Cell Culture...............................................8
Morphology Observation.....................................8
MTT Viability Test.........................................8
Cell Cycle Analysis........................................9
Annexin V/PI Double Staining Assay.........................9
Protein Extraction and Western Blotting Analysis..........10
Mitochondrial Protein Isolation...........................11
The Measurement of Intracellular ROS Generation...........11
Statistical Analysis......................................12
The morphological changes of MA-10 cells after treatment with arsenic compounds....................................13
Arsenic compounds decreased MA-10 cell viability in time- and dose-dependent manners................................13
Arsenic compounds induced apoptosis in MA-10 cells........14
Arsenic-induced MA-10 cell apoptosis was mediated by caspase cascade...................................................15
Caspase inhibitor reversed arsenic-induced MA-10 cell apoptosis.................................................16
The different effects of arsenic compounds on the expression of Fas ligand.............................................17
The release of cytochrome C and translocation of Bcl-2 family proteins in arsenic-induced MA-10 cell apoptosis...17
Long-term arsenic exposure induced activation of MAPK pathways (ERK1/2, JNK and p38) ...........................19
Arsenic compounds decreased the phosphorylation and the expression of Akt protein.................................19
Arsenic compounds induced ROS generation during MA-10 cell apoptosis.................................................20
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