Bortezomib abolishes tumor necrosis factor-related apoptosis-inducing ligand resistance via a p21-dependent mechanism in human bladder and prostate cancer cells
Bortezomib abolishes tumor necrosis factor-related apoptosis-inducing ligand resistance via a p21-dependent mechanism in human bladder and prostate cancer cells
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DOI：
10.1158/0008-5472.can-04-3701
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发表时间：
2005-06-01
期刊：
影响因子：
11.2
通讯作者：
McConkey, DJ
中科院分区：
文献类型：
--
作者：
Lashinger, LM;Zhu, K;McConkey, DJ
肿瘤坏死因子相关的凋亡诱导配体(TRAIL)是肿瘤坏死因子家族中的一员，可诱导某些肿瘤细胞的凋亡，但不能诱导正常细胞的凋亡。不幸的是，许多人类癌细胞系对TRAIL诱导的细胞死亡是耐药的，其耐药的分子机制尚不清楚。在这里，我们报告了蛋白酶体抑制剂Bortezomib(PS-341，VELCADE)逆转了人膀胱和前列腺癌TRAIL耐药。联合应用TRAIL和硼替佐米可在4~6h内协同诱导细胞凋亡，并与p21(WAF-1/Cip-1)(P21)积聚和抑制细胞周期蛋白依赖性激酶(Cdk)活性有关。罗索维汀是一种特异性的CDK1/2抑制剂，也能使细胞对TRAIL敏感。抑制p21的表达可使经Bortezomib和TRAIL处理的细胞DNA片段化水平降低50%)，证实p21是该反应所必需的。对TRAIL通路的分析表明，与单独使用TRAIL相比，TRAM和Bortezomib处理细胞中caspase-8的处理以p21依赖的方式增强。因此，该途径的所有下游成分(Bid裂解、细胞色素c释放和caspase-3激活)都被扩增。这些数据有力地表明，p21介导的cdk抑制通过激活caspase-8促进TRAIL的敏感性，TRAIL和Bortezomib应该在适当的体内模型中联合作为实体瘤治疗的可能方法。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines that induces apoptosis in some tumor cells but not in normal cells. Unfortunately, many human cancer cell lines are refractory to TRAIL-induced cell death, and the molecular mechanisms underlying resistance are unclear. Here we report that TRAIL resistance was reversed in human bladder and prostate cancer cell lines by the proteasome inhibitor bortezomib (PS-341, Velcade). Synergistic induction of apoptosis occurred within 4 to 6 hours in cells treated with TRAIL plus bortezomib and was associated with accumulation of p21(WAF-1/Cip-1) (p21) and inhibition of cyclin-dependent kinase (cdk) activity. Roscovitine, a specific cdk1/2 inhibitor, also sensitized cells to TRAIL. Silencing p21 expression reduced levels of DNA fragmentation by 50%) in cells treated with bortezomib and TRAIL, confirming that p21 was required for the response. Analysis of the TRAIL pathway revealed that caspase-8 processing was enhanced in a p21-dependent fashion in cells exposed to TRAM and bortezomib as compared with cells treated with TRAIL alone. Thus, all downstream components of the pathway (Bid cleavage, cytochrome c release, and caspase-3 activation) were amplified. These data strongly suggest that p21-mediated cdk inhibition promotes TRAIL sensitivity via caspase-8 activation and that TRAIL and bortezomib should be combined in appropriate in vivo models as a possible approach to solid tumor therapy.