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.

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