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研究生:張福林
研究生(外文):Fu-Lin Chang
論文名稱:探究p53蛋白於抗癌藥物引發之膀胱癌細胞凋亡過程中扮演之角色
論文名稱(外文):The role of p53 in the apoptosis induced by anticancer drugs in bladder cancer cells
指導教授:賴明德賴明德引用關係
指導教授(外文):Ming-Derg Lai
學位類別:博士
校院名稱:國立成功大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:145
中文關鍵詞:p53蛋白抗癌藥物細胞凋亡
外文關鍵詞:cisplatinapoptosistumor suppressor gene
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已知抗癌藥物常藉細胞凋亡作用殺死癌細胞,但以往對於p53蛋白與腫瘤細胞化療敏感性之間的關係研究結論並不一致。臨床研究顯示,當膀胱癌病人的腫瘤細胞具有野生型 p53時,病人於腫瘤切除後進行的輔助性化學療法並無法對其復發率與存活率有所助益,反倒是當病人的腫瘤細胞具有突變型p53時,輔助性化學療法可降低病人日後膀胱癌復發的機率、並使存活機會增加。我們在in vitro進行的實驗結果指出:當膀胱癌細胞受到抗癌藥物處理後,細胞凋亡現象並不祇出現在具有野生型p53的膀胱癌細胞株中,而且當細胞同時具有野生型及突變型p53蛋白時凋亡現象最為明顯。當我們在人類膀胱癌細胞株TCCSUP (缺乏全長野生型p53蛋白) 中建立五種持續表現不同突變型態p53蛋白 (V143A, V173L, H179Q, N247I, and R273L) 的穩定細胞株後,發現除了p53 R273L這一種突變型式的轉染細胞株之外,其他p53突變型式的轉染細胞株對adriamycin及cisplatin二種藥物皆表現出較佳的藥物感受性;且進一步由TUNEL分析法、annexin-Ⅴ分析法與Hoechst分析法發現,細胞受到cisplatin處理後,主要經由 ”細胞凋亡” 的方式死亡,但以adriamycin處理之細胞則是經由 ”非細胞凋亡” 的方式死亡。

為了瞭解突變型p53蛋白如何促進細胞凋亡?接下來我們著手分析細胞內訊息傳遞的機轉,由我們的實驗結果看來:細胞受到cisplatin處理後,突變型p53蛋白亦如野生型 p53蛋白於serine15位置被kinase磷酸化,但野生型p53蛋白的乙醯化程度在cisplatin處理後會增加,而突變型p53 蛋白的乙醯化程度卻降低了。此外、突變型p53蛋白並未改變細胞膜表面Fas與FasL的表現量,它也未活化caspase-8,而是藉由caspase 9的活化來促成細胞凋亡。p53下游基因Noxa、 p53R2與 PIDD在cisplatin處理的過程中皆未見明顯活化,Bcl-2 雖然被抑制,但於加入histone deacetylase inhibitor trichostatin A (TSA) 挽回Bcl-2 抑制時,並無法阻止cisplatin引發的凋亡作用。加入actinomycin D與cycloheximide並無法阻止cisplatin所引起的細胞凋亡,顯示突變型p53所促進的細胞凋亡作用並不需要經由transactivate下游基因的表現來促成
Many antitumor agents may kill cells by induction of apoptosis. However, the relationship between the status of p53 and the sensitivity of tumors to anticancer treatment is somewhat more complex. Clinical studies showed that, in patients with bladder tumors that did not demonstrate p53 alterations, adjuvant chemotherapy conferred no recurrence or survival benefit. In contrast, in patients with p53-altered tumors, adjuvant chemotherapy resulted in a decreased risk of recurrence and a increased chance of surviving. These data imply that bladder tumor cells harboring mutant p53 are possibly prone to death during drug treatment. In our in vitro studies, we found that anticancer drugs-induced apoptosis in bladder cancer cells is independent of the presence of wild-type p53. Indeed, tumor cells harboring heterozygous mutant p53 seem to be most susceptible to undergo apoptosis. When the various p53 mutants (V143A, V173L, H179Q, N247I, and R273L) were stably transfected into the TCCSUP bladder carcinoma cell line (no endogenous full-length mutant p53), almost all mutant p53 transfectants were more sensitive to adriamycin and cisplatin except for the p53Leu273 mutant. Adriamycin and cisplatin induced cell death was assayed by TUNEL, annexin-Ⅴ and Hoechst staining. Our results show that cisplatin-induced cell death is mediated mainly through apoptosis, while adriamycin-induced cell death probably occurs through a non- apoptotic pathway.
In order to understand how mutant p53 promotes apoptosis in bladder cancer cells?We investigate the mechanism of the enhancement of cisplatin-induced apoptosis by exogenous mutant p53. We found that both wild-type and mutant p53 was phosphorylated at serine15 in response to cisplatin. However, the acetylation of mutant p53 decreased, in contrast to the acetylation of wild-type p53 increased during the treatment of cisplatin. Besides that, mutant p53 did not alter surface Fas and Fas-L expression. They amplified cisplatin-induced apoptosis mainly through activation of caspase-9 but not caspase-8. On the other hand, several p53-inducible genes (Noxa, p53R2 and PIDD) were not activated during cisplatin treatment. Down-regulation of Bcl-2 was observed, it could be reversed by the addition of histone deacetylase inhibitor trichostatin A (TSA), but the apoptosis proceeds as usual. Transcriptional inhibitor actinomycin D and translational inhibitor cycloheximide were unable to impede the apoptosis induced by cisplatin in these transfectants. These results indicated that enhanced apoptosis by mutant p53 was independent of transcriptional activation and translation of p53-related target genes.
目錄 Ⅰ
縮寫表 Ⅳ
中文摘要 Ⅵ
英文摘要 Ⅷ
第一章 序論
1. 膀胱癌 1
2. 膀胱癌之化學療法 2
3. 細胞凋亡 (apoptosis) 的徵候 5
4. 細胞凋亡之機轉 5
Caspases 5
Bcl-2 family members 7
Mitochondria 8
哺乳類細胞中兩條主要的凋亡路徑 9
5. 腫瘤抑制基因p53與癌症 11
6. p53蛋白質之結構 12
7. p53蛋白質之活化及其生理功能 14
8. p53蛋白質如何引起細胞凋亡 17
9. 研究目的 20
第二章 材料與方法
1. 材料 22
2. 細胞株與細胞培養 26
3. PCR引子 28
4. 表現質體 (Expression plasmids) 29
5. 勝任細胞的製備 (Preparation of competent cell) 30
6. 細菌轉形 (Transformation) 31
7. 小量質體的製備 (Mini-prep of plasmid) 31
8. 大量質體的製備 (Maxi-prep of plasmid) 32
9. DNA片段回收法 (Recovery of DNA fragment from agarose gel) 32
10. 建立持續表現mutant p53的人類膀胱癌細胞株 33
11. RNA的抽取 (RNA isolation) 34
12. 反轉錄-聚合酶連鎖反應 (RT-PCR) 35
13. 免疫細胞化學染色 (Immunocytochemical staining) 35
14. 西方墨點分析法 (Western Blot) 36
15. 細胞存活率的測量 (Trypan blue exclusion) 37
16. 生長速率分析-MTT assay 38
17. DNA萃取及瓊膠電泳偵測凋亡 (DNA fragmentation Assay) 38
18. MC 540染色分析法 (MC 540 Staining Procedure) 39
19. 細胞核型態之觀察 (Hoechst 33258 stain) 40
20. Annexin-Ⅴ染色分析法 40
21. TUNEL分析法 41
22. 細胞週期的分析 (cell cycle analysis) 42
23. 偵測細胞表面Fas的表現 (surface Fas expression assay) 43
24. 偵測細胞表面FasL的表現 (surface FasL expression assay) 44
25. 免疫沈澱法 (Immunoprecipitation) 45
第三章 結果
1. 人類膀胱癌細胞株所表現的p53蛋白種類與細胞凋亡現象間
無明確相關性 47
2. 建立持續表現突變型p53蛋白的轉染細胞株 48
3. 持續表現突變型p53蛋白的轉染細胞株對cisplatin及adriamycin
(doxorubicin) 敏感性皆增加 50
4. cisplatin與adriamycin誘發細胞經由兩種不同的方式死亡 50
5. 細胞週期的分析 53
6. cisplatin誘發細胞凋亡的過程中發生Bcl-2 down-regulation 54
7. histone deacetylase inhibitor無法抑制cisplatin引發的凋亡作用 55
8. 突變型p53蛋白 (V143A與N247I) 藉由Caspase 9來促進細胞凋亡 55
9. 突變型p53蛋白並未改變細胞膜表面Fas與FasL的表現量 56
10. Noxa, p53R2, PIDD在cisplatin處理細胞的過程中並未明顯地活化 57
11. cisplatin處理後,野生型p53蛋白與突變型p53蛋白皆於serine 15
產生磷酸化現象 57
12. cisplatin處理後,野生型p53蛋白的乙醯化程度增加,而突變型p53
蛋白的乙醯化程度卻降低了 58
13. 突變型p53蛋白所促成的細胞凋亡作用是transcription-independent與translation-independent 59
14. 野生型p53蛋白位於核仁中,而突變型p53蛋白位於核質中 59
第四章 討論
1. 抗癌藥物不祇在表現wild-type p53的人類膀胱癌細胞株誘發細胞凋亡 61
2. 表現突變型p53蛋白的轉染細胞株具有較佳的藥物感受性 63
3. cisplatin與 adriamycin (doxorubicin) 經由兩種不同的方式誘發膀胱
癌轉染細胞株死亡 64
4. 突變型p53蛋白促進cisplatin-induced apoptosis可能的機轉 66
5. 野生型p53蛋白與突變型p53蛋白在膀胱癌細胞核中分佈的位置不同 71
第五章 圖表 73
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