Role of XIAP in the malignant phenotype of transitional cell cancer (TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistant TCC in vitro
Role of XIAP in the malignant phenotype of transitional cell cancer (TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistant TCC in vitro
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DOI：
10.1002/ijc.10776
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发表时间：
2003-01-01
影响因子：
6.4
通讯作者：
Tomita, Y
中科院分区：
文献类型：
--
作者：
Bilm, V;Kasahara, T;Tomita, Y
XIAP直接抑制执行caspase，使其成为最下游的抗凋亡分子。在此，我们研究了XIAP在正常尿路上皮和膀胱移行细胞癌中的表达和功能。我们还检测了Xiap AS PODN对多药耐药的T24膀胱癌细胞的细胞周期和凋亡的治疗作用。XIAP在正常膀胱移行上皮中呈中等表达，在浅表层细胞中表达显著。108例肿瘤组织中79例（73.15%）XIAP蛋白阳性，但XIAP阳性率与肿瘤分期、分级无关。此外，4种膀胱癌细胞系（SCaBER、HT 1376、T24和RT 4）表达相似水平的XIAP。XIAP AS PODN剂量依赖性地降低XIAP蛋白水平并诱导凋亡，导致细胞活力降低87%。与多柔比星联合给药由于细胞凋亡的升级导致显著的细胞毒性。与亲本细胞相比，XIAP在T24细胞中的过表达导致适度但统计学显著（p < 0.01）的存活优势。因此，XIAP表达对于维持TCC的活力和耐药性可能是关键的，并且内源性XIAP水平足以保护细胞免于凋亡。我们的研究结果表明，XIAP可能在人类TCC癌变的早期发挥重要作用。Xiap AS可能是用作克服高度恶性TCC的耐药性的癌症疗法的候选者。(C)2002 Wiley-Liss，Inc.
XIAP directly inhibits executor caspases, making it the most downstream antiapoptotic molecule. Here, we examined the expression and function of XIAP in normal urothelium and TCC. We also examined the therapeutic effect of xiap AS PODN on the cell cycle and apoptosis of multidrug-resistant T24 bladder cancer cells. XIAP was moderately expressed in normal transitional epithelium with prominent expression on the superficial layer cells. Seventy-nine of 108 (73.15%) tumor samples were positive for XIAP protein, but XIAP positivity was not correlated with tumor stage or grade. Moreover, 4 bladder cancer cell lines (SCaBER, HT 1376, T24 and RT4) expressed similar levels of XIAP. xiap AS PODN dose-dependently reduced the XIAP protein level and induced apoptosis, leading to decreased cell viability by 87%. Combined administration with doxorubicin resulted in marked cytotoxicity due to escalation of apoptosis. Overexpression of XIAP in T24 cells resulted in a modest but statistically significant (p < 0.01) survival advantage compared to parental cells. Thus, XIAP expression may be critical for maintaining the viability and drug resistance of TCC, and endogenous XIAP levels are sufficient to protect cells from apoptosis. Our results suggest that XIAP may play an important role early in human TCC carcinogenesis. xiap AS may be a candidate for use as a cancer therapy for overcoming drug resistance in highly malignant TCC. (C) 2002 Wiley-Liss, Inc.