Oxaliplatin down-regulates survivin by p38 MAP kinase and proteasome in human colon cancer cells
Oxaliplatin down-regulates survivin by p38 MAP kinase and proteasome in human colon cancer cells
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DOI：
10.1016/j.cbi.2010.08.001
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发表时间：
2010-12-05
影响因子：
5.1
通讯作者：
Chao, Jui-I
中科院分区：
文献类型：
--
作者：
Liu, Huei-Fang;Hu, Huai-Chin;Chao, Jui-I
奥沙利铂是一种铂类抗癌药物，已被用于治疗人类结直肠癌。Survivin已被认为是一种肿瘤靶点，它在大多数癌细胞中高表达，但在正常成人细胞中不表达。在这项研究中，我们研究了奥沙利铂对人结肠癌细胞Survivin表达的调节。奥沙利铂(3~9 mU M作用24 h)对人RKO结肠癌细胞有明显的细胞毒作用、增殖抑制作用和细胞凋亡作用。奥沙利铂可显著降低RKO细胞Survivin蛋白的表达，但对Survivin基因的表达影响不大。奥沙利铂阻断Survivin可提高RKO细胞caspase-3活性和细胞凋亡率。用Survivin表达载体过表达Survivin蛋白可抵抗奥沙利铂诱导的癌细胞死亡。同时，奥沙利铂可诱导p38丝裂原活化蛋白(MAP)激酶的磷酸化。特异性p38 MAPK抑制剂SB202190可恢复Survivin蛋白水平，减轻奥沙利铂诱导的癌细胞死亡。此外，奥沙利铂还增加了P53磷酸化水平(Ser-15)和总P53蛋白水平。抑制p53蛋白表达的P53抑制剂匹非菊酯-α降低了草酸铂暴露的RKO细胞中磷酸化的p38蛋白和活化的caspase-3蛋白。相反，SB202190不改变奥沙利铂诱导的P53蛋白水平。此外，用特定的蛋白酶体抑制剂MG132治疗恢复了奥沙利铂治疗的结肠癌细胞中的Survivin蛋白水平。综上所述，我们的结果首次证明了奥沙利铂处理人结肠癌细胞后，Survivin被p38蛋白激酶和蛋白酶体降解途径下调。(C)2010爱思唯尔爱尔兰有限公司。保留所有权利。
Oxaliplatin, a platinum derivative cancer drug, has been used for treating human colorectal cancers. Survivin has been proposed as a cancer target, which highly expressed in most cancer cells but not normal adult cells. In this study, we investigated the regulation of survivin expression by exposure to oxaliplatin in human colon cancer cells. Oxaliplatin (3-9 mu M for 24 h) markedly induced cytotoxicity, proliferation inhibition and apoptosis in the human RKO colon cancer cells. The survivin protein expression of RKO cells is dramatically reduced by oxaliplatin; however, the survivin gene expression is slightly altered. The survivin blockage of oxaliplatin elevated caspase-3 activation and apoptosis in RKO cells. Over-expression of survivin proteins by transfection with a survivin-expressed vector resisted the oxaliplatin-induced cancer cell death. Meantime, oxaliplatin elicited the phosphorylation of p38 mitogen-activated protein (MAP) kinase. SB202190, a specific p38 MAP kinase inhibitor, restored the survivin protein level and attenuated oxaliplatin-induced cancer cell death. In addition, oxaliplatin increased the levels of phospho-p53 (Ser-15) and total p53 proteins. Inhibition of p53 expression by a specific p53 inhibitor pifithrin-alpha reduced the phosphorylated p38 MAP kinase and active caspase-3 proteins in the oxaliplatin-exposed RKO cells. In contrast, SB202190 did not alter the oxaliplatin-induced p53 protein level. Furthermore, treatment with a specific proteasome inhibitor MG132 restored survivin protein level in the oxaliplatin-treated colon cancer cells. Taken together, our results demonstrate for the first time that survivin is down-regulated by p38 MAP kinase and proteasome degradation pathway after treatment with oxaliplatin in the human colon cancer cells. (C) 2010 Elsevier Ireland Ltd. All rights reserved.