摘要
p53的狀態與腫瘤細胞對抗癌藥物敏感度之關連性似乎遠比想像的複雜。Cote et al.曾於臨床上觀察膀胱癌患者，其腫瘤未含突變型p53者，化療效果並不因此而對其生存年限有所助益；相對來說，在腫瘤帶有突變型p53之患者經化學治療後，能提高2.6倍的生存年數。
因此我們實驗室將各種形式的突變型p53 (V143A、V173L、H179Q、N247I以及R273H)送入膀胱癌細胞-TCCSUP中，建立持續表現的轉染細胞株，並以抗癌藥物cisplatin處理。發現除了其中之一的突變型p53的轉染細胞株TCCSUP-273之外，其餘TCCSUP-143、TCCSUP-173、TCCSUP-179與TCCSUP-247四種細胞株均較於原本的TCCSUP細胞，對藥物有較高的敏感性。並證實cisplatin是以細胞凋亡(apoptosis)作用造成細胞死亡。
而p53可透過三種模式來執行其功能：(1)轉錄作用而促進目標基因(如：PIDD、p53R2、NOXA等)表現(2)轉錄作用而抑制目標基因(如：survivin、cyclin B2等)表現(3)蛋白質之間的交互作用，如調控Fas的移動或p53本身的移動。本研究即依其三種模式，一一檢驗突變型p53可能作用的機制。
利用semiquantitative RT-PCR去檢驗三個能被p53啟動而轉錄的基因：PIDD、p53R2及NOXA，觀察在突變型p53的轉染細胞株中這些基因的表現。實驗結果顯示，p53R2及NOXA這兩個基因在TCCSUP、TCCSUP-143、TCCSUP-247及TCCSUP-273中表現情況均為相似；而PIDD基因，相較於TCCSUP-143、TCCSUP-247及TCCSUP-273，在TCCSUP細胞中則有明顯被誘導表現的情況，配合實驗室過去曾以轉錄作用抑制劑actinomycin D先行處理再觀察這些細胞對cisplatin高敏感性的現象是否消失，但結果顯示，這樣的作法並不影響TCCSUP-143、TCCSUP-247容易死亡的現象。故p53可能並非是藉由轉錄作用而促進目標基因的方式來執行其功能。
兩個可能影響p53抑制基因功能的histone deacetylases (HDACs) inhibitor：trichostatin A (TSA)及nicotinamide (NA)被用來檢驗是否能使突變型p53造成高敏感的現象消失。Trichostatin A的處理同時加強了細胞的TCCSUP或TCCSUP-143的死亡，因此突變型p53的轉染細胞株對cisplatin高敏感性的現象仍然存在。而nicotinamide的處理，不影響TCCSUP卻使TCCSUP-143的存活情形有部分回升的現象，使TCCSUP-143對藥物的敏感性變得與TCCSUP接近。然而以Semi-quantitative RT-PCR分析兩個能被p53抑制的基因：survivin及cyclin B2其表現在四種細胞中相似，均呈現被抑制的情形。這些結果顯示p53可能藉由其它抑制的基因或是nicotinamide的處理影響了細胞凋亡進行過程中的蛋白質間交互作用的作用而產生敏感度改變的現象。
使用專門辨識N端epitope的抗體，可觀察到cisplatin處理後，bak蛋白質N端會發生構形改變但bax蛋白質則無此現象，且敏感度高的細胞株(TCCSUP-143 and TCCSUP-247)具較明顯之構形變化。以粒線體染劑JC-1偵測藥物處理後膜電位的變化，在敏感度高的細胞中可觀察到粒線體膜電位下降的情形。除此之外，處理nicotinamide不但能減緩bak蛋白質N端構形改變的情況，亦能阻止膜電位的下降。如此的結果暗示bak蛋白質N端構形改變可能在突變型p53誘發細胞凋亡中扮演角色。
在本研究中，我們認為突變型p53可能藉由bak蛋白質N端構形改變，而啟動粒線體細胞凋亡之機制，使得外送突變型p53於膀胱癌細胞株TCCSUP對抗癌藥物cisplatin產生高敏感性的現象。

Abstract
The relationship between the status of p53 and the sensitivity of tumors to anticancer treatment is somewhat complex. Cote et al. reported that in patients with bladder tumors that did not demonstrate p53 alterations, adjuvant chemotherapy conferred no survival benefit. In contrast, in patients with p53-altered tumor, adjuvant chemotherapy resulted in 2.6 fold-increased chance of surviving.

Our lab delivered several mutant p53 (V143A, V173L, H179Q, N247I and R273H) into bladder cancer cell line-TCCSUP, and studied the response to anticancer drug-cisplatin (CDDP) in these transfectants. All forms of mutant p53 except p53-R273H enhanced sensitivity to this drug. The sensitivity of p53-R273H transfectant was similar to that of parental TCCSUP. And cisplatin induced cell death through apoptosis.

p53 can exert its function through three possible pathways: (1) transcriptional activation of downstream target genes: PIDD, p53R2; NOXA et al.; (2) transcriptional repression of downstream target genes; survivin, cyclin B2 et al.; (3) protein-protein interaction, such as surface trafficking of Fas or localization of p53. We investigated the possibility of three pathways in this research.

The expression of p53 target genes, p53R2 and NOXA, had similar patterns in parental cell and mutant p53 transfectants. Another gene, PIDD, was induced in parental cell more than transfectants. Consistent with our previous research, addition of transcriptional inhibitor, actinomycin D, did not prohibit the cell from cisplatin-induced apoptosis. These results indicated that enhanced-apoptosis by mutant p53 was unlikely to mediate through transcriptional activation.

Histone deacetylases (HDACs) inhibitor, trichostatin A (TSA), and nicotinamide (NA), were assayed to reverse the mutant-p53 induced apoptosis. Treatment cell with trichostatin A and cisplatin enhanced the cisplatin-induced apoptosis whether in TCCSUP or TCCSUP-143. Treatment of cells with nicotinamide and cisplatin recovered cisplatin-induced apoptosis in TCCSUP-143. This treatment rendered sensitivity of TCCSUP-143 close to parental cell TCCSUP. Semi-quantitative RT-PCR was used to analyze the expression of p53 down-regulation genes, survivin, cyclin B2. However, both of two genes still showed the similar patter in these four cell lines. These results suggest that other p53-target genes or direct protein-protein interaction influence apoptotic process.

With conformation-specific antibody, we observed the N-terminal conformation change of bak but not bax in all cell lines. Significant conformation change was observed in TCCSUP-143 and TCCSUP-247, which were more sensitive to cisplatin. A mitochondrial potential sensors “JC-1” was used to measure the mitochondrial membrane potential. The membrane potential decreased in TCCSUP-143 and TCCSUP-247. Treatment with histone deacetylase inhibitor nicotinamide not only reduced level of conformation change, but also restored the membrane potential in TCCSUP-143. It indicates the conformation change may play a role in the mechanism of mutant p53 enhanced cisplatin-induced apoptosis.

In conclusion, apoptosis may be induced through the N-terminal conformation change of bak and then undergoes the mitochondrial pathway. It is one of mechanisms that mutant p53 enhanced cisplatin-induced apoptosis in the bladder cancer cell line TCCSUP.

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