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研究生:鄭瑋婷
研究生(外文):Wei-Ting Cheng
論文名稱:Bcl-xL去醯胺基化與癌細胞對Cisplatin的敏感性呈正相關
論文名稱(外文):Bcl-xL Deamidation of Cancer Cells Correlates with Cisplatin-induced Cytotoxicity
指導教授:陳一村
指導教授(外文):I-Tsuen Chen
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:73
中文關鍵詞:去醯胺基化cisplatinBcl-xL
外文關鍵詞:deamidationcisplatinBcl-xL
相關次數:
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近年來有研究指出,DNA損傷抗癌藥物可引起癌症細胞之Bcl-xL去醯胺基化,去醯胺基化後的Bcl-xL會失去抗凋亡活性,導致細胞凋亡;另人驚訝的是,這樣的現象會受到Rb的表現而抑制。在我們之前的研究中也發現,E1A可經由與Rb作用使卵巢癌細胞 (SKOV3.ip1) 對cisplatin敏感並引起Bcl-xL去醯胺基化。此外,證實了送入去醯胺基化的Bcl-xL (N52/66D) 到卵巢癌細胞中會促進細胞凋亡;而無法去醯胺基化的Bcl-xL (N52/66A) 則可保護細胞抵抗E1A引起的cisplatin敏感化。延續上述的實驗,在此我們觀察到去醯胺基化作用並不影響Bcl-xL與Bad之間的結合關係,而且外送p53至SKOV3.ip1細胞中,對cisplatin引起的細胞死亡和Bcl-xL去醯胺基化程度並無明顯影響。接著我們觀察四種Rb和p53基因表現狀態不同的癌細胞株,發現cisplatin引起之Bcl-xL去醯胺基化與細胞對cisplatin敏感程度密切相關,而且表現E1A並無法促使對cisplatin有抗藥性細胞 (wild-typed Rb) 之Bcl-xL去醯胺基化。在體外鹼性pH實驗中發現所有細胞都可被引起高比率的Bcl-xL去醯胺基化,由此推論,上述對cisplatin有抗藥性的細胞中無法引起Bcl-xL去醯胺基化的原因並非由於胺基酸52和66位置上發生突變所致。此外,Bcl-2的表現量在對cisplatin敏感與有抗藥性的細胞中有很大的差異,Bcl-2表達高則細胞抗藥性也高。最後,我們發現抗氧化劑N-acetylcysteine (NAC) 可阻斷cisplatin引起之Bcl-xL去醯胺基化和細胞凋亡,推測cisplatin引起Bcl-xL去醯胺基化的機制可能與ROS亦有關。
Previous studies have shown that chemotherapy causes deamidation of the protein Bcl-xL in tumor cells. This Bcl-xL deamidation inhibits its antiapoptotic ability and sensitizes tumor cells to cisplatin treatment. Surprisingly, Rb inhibits this process. To test this model, we have shown recently that E1A-mediated Rb inactivation in an ovarian cancer cell line (SKOV3.ip1) leads to Bcl-xL deamidation which contributes to cisplatin-induced apoptosis. Furthermore, ectopic expression of deamidated form of Bcl-xL (N52/66D) enhances cell death, whereas the nondeamidated Bcl-xL (N52/66A) protects E1A-mediated apoptosis. In this follow-up studies, we showed that BH3 protein bad interacts equally well with all three forms of Bcl-xL protein. In addition, ectopic expression of p53 did not enhance cell death or Bcl-xL deamidation in SKOV3.ip1. To test whether Bcl-xL deamidation occurs in other cancer cells, we selected four cancer cell lines with various Rb and p53 status. Our data show that the cell lines sensitive to cisplatin correlated with induction of Bcl-xL deamidation, whereas the cell lines resistant to cisplatin exhibited no induction of Bcl-xL deamidation. Interestingly, expression of E1A did not sensitize the cisplatin-resistant cell lines or Bcl-xL deamidation. Both the cisplatin-resistant cell lines are Rb wt. Furthermore, In vitro alkaline treatment induced Bcl-xL deamidation in these cell lines, suggesting that no induction of Bcl-xL deamidation in the cisplatin- resistant cell lines is not due to mutation of Bcl-xL at 55 and 66 residues. We also noticed that level of Bcl-2 was higher in the cisplatin-resistant cells than in the cisplatin-sensitive cells. Moreover, we found that N-acetylcysteine protected cells from cisplatin induced apoptosis and repressed Bcl-xL deamidation. This suggested that reactive oxygen species (ROS) may be involved in the induction of Bcl-xL deamidation by cisplatin.
目錄
摘要 3
Abstract 4
壹、緒論 6
順-雙胺雙氯鉑 (cisplatin) 6
E1A (Human adenovirus-5 early gene 1A) 7
Rb and E2F 9
Bcl-xL and Bad 11
Protein deamidation 12
Bcl-xL deamidation 13
貳、材料與實驗方法 16
一、材料 16
(一)細胞株: 16
(二)細胞培養材料: 16
(三)藥品: 17
(四)質體(plasmids): 17
(五)Markers: 17
(六)Membrane and Filter Paper: 18
(七)Kit, Reagents and Chemicals: 18
(八)抗體: 19
二、實驗方法 19
(一)細胞培養與操作 19
(二)轉型作用(Transformation) 21
(三)質體DNA製備(Plasmid DNA midi preparation) 21
(四)暫時性轉殖(Transient transfectoin) 22
(五)免疫沉澱(Immunoprecipitation) 23
(六)西方墨點法(Western blot) 23
(七)細胞存活率分析(MTT assay) 26
(九)Phosphatase的處理 27
(十)Bcl-xL deamidation ratio的計算法 27
參、實驗結果 28
一、Bcl-xL去醯胺基化後仍與凋亡蛋白Bad結合 28
二、異位性表現p53並不造成卵巢癌細胞 (p53-null;wild-type Rb) 的死亡。 29
三、異位性表現p53會選擇性抑制癌症細胞的增殖 29
四、異位性表現p53不影響cisplatin引起卵巢癌細胞之Bcl-xL去醯胺基化 30
五、在不同的癌細胞株中cisplatin引發不同程度的細胞死亡 31
六、Bcl-xL去醯胺基化與否與細胞對cisplatin的敏感度有關 32
七、 H1299和BT474細胞株中,暫時轉殖表現E1A無法促使cispaltin引起Bcl-xL去醯胺基化 32
八、在鹼性環境中Bcl-xL去醯胺基化明顯增加 33
九、Cisplatin引起之Bcl-xL修飾並非磷酸化作用(phosphorylation) 34
十、H1299和BT474兩株細胞具有高表達的Bcl-2蛋白 35
十二、N-Acetylcysteine保護細胞免於受到cisplatin傷害而凋亡 35
肆、實驗討論 37
伍、參考文獻 43
陸、圖表 54
附錄一 65
附錄二 67
附錄三 73
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