標題: Oxaliplatin down-regulates survivin by p38 MAP kinase and proteasome in human colon cancer cells
作者: Liu, Huei-Fang
Hu, Huai-Chin
Chao, Jui-I
分子醫學與生物工程研究所
Institute of Molecular Medicine and Bioengineering
關鍵字: Survivin;p38 MAP kinase;Proteasome;Oxaliplatin;Apoptosis
公開日期: 5-Dec-2010
摘要: 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.
URI: http://dx.doi.org/10.1016/j.cbi.2010.08.001
http://hdl.handle.net/11536/26245
ISSN: 0009-2797
DOI: 10.1016/j.cbi.2010.08.001
期刊: CHEMICO-BIOLOGICAL INTERACTIONS
Volume: 188
Issue: 3
起始頁: 535
結束頁: 545
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