Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa
Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa
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DOI：
10.1074/jbc.m604356200
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发表时间：
2006-10-20
影响因子：
4.8
通讯作者：
Wang, Cun-Yu
中科院分区：
文献类型：
--
作者：
Fribley, Andrew M.;Evenchik, Benjamin;Wang, Cun-Yu
顺铂是用于治疗患有实体瘤如鳞状细胞癌（SCC）的患者的最常见的DNA损伤剂之一。不幸的是，SCC细胞在顺铂治疗后迅速出现显著水平的耐药性。在这里，我们报告的蛋白酶体抑制剂PS-341，一类新的化疗药物的代表，能够诱导凋亡顺铂耐药SCC细胞通过内质网应激。PS-341刺激PERK的磷酸化和未折叠蛋白反应，导致转录因子ATF-4的诱导。重要的是，Bcl-2同源结构域3-only（BH 3-only）蛋白Noxa被发现在顺铂耐药SCC细胞中被PS-341强烈诱导，而不是顺铂。使用小干扰RNA敲低Noxa显著消除了PS-341介导的SCC细胞凋亡。使用eIF 2 α突变的小鼠胚胎成纤维细胞，我们发现功能性eIF 2 α在PS-341诱导的Noxa表达中发挥重要作用。综上所述，我们的新发现揭示了PS-341诱导的内质网应激和细胞凋亡依赖性途径之间的直接联系，并表明PS-341可用于克服顺铂耐药的人SCC。
Cisplatin is one of the most common DNA-damaging agents used for treating patients with solid tumors such as squamous cell carcinoma (SCC). Unfortunately, significant levels of resistance in SCC cells emerge rapidly following cisplatin treatment. Here we report that the proteasome inhibitor PS-341, the representative of a new class of chemotherapeutic drugs, was capable of inducing apoptosis in cisplatin-resistant SCC cells via the endoplasmic reticulum stress. PS-341 stimulated the phosphorylation of PERK and the unfolded protein response, resulting in the induction of the transcription factor ATF-4. Importantly, the Bcl-2 homology domain 3-only (BH3-only) protein Noxa was found to be strongly induced in cisplatin-resistant SCC cells by PS-341 but not by cisplatin. The knock-down of Noxa using small interference RNA significantly abolished PS-341-mediated apoptosis in SCC cells. Using eIF2 alpha mutant mouse embryonic fibroblasts, we found that functional eIF2 alpha played an essential role in PS-341-induced Noxa expression. Taken together, our novel findings reveal a direct link between PS-341-induced endoplasmic reticulum stress and the mitochondria-dependent apoptotic pathway and suggest that PS-341 may be utilized for overcoming cisplatin-resistance in human SCC.