Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells
Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells
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DOI：
10.1002/ijc.20304
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发表时间：
2004-11-01
影响因子：
6.4
通讯作者：
Maehara, Y
中科院分区：
文献类型：
--
作者：
Maehara, S;Tanaka, S;Maehara, Y
吉西他滨是一种新的用于胰腺癌治疗的标准化疗药物，但吉西他滨的敏感性机制仍存在争议。为了确定调控吉西他滨敏感性的机制，我们对胰腺癌细胞的易感性进行了分子分析。使用吉西他滨敏感的胰腺癌细胞系KLMI，我们建立了耐药细胞系KLMI- r，其ic50值为20倍（吉西他滨浓度导致50%的生长抑制）。基因微阵列分析显示，抗氧化剂硒蛋白P在KLMI- r细胞株中有特异性表达，而在KLMI细胞株中无特异性表达。硒蛋白P可抑制吉西他滨诱导的胰腺细胞毒性。吉西他滨增加了KLMI细胞内活性氧（ROS）水平，但硒蛋白P抑制了吉西他滨诱导的ROS水平。此外，干扰素抑制硒蛋白P mRNA的表达，增加细胞内ROS水平，导致KLMI-R对吉西他滨的敏感性恢复。这些结果提示了一种新的机制，硒蛋白P降低细胞内ROS水平，导致对吉西他滨不敏感。(C) 2004 Wiley-Liss, Inc。
Gemcitabine is a new standard chemotherapeutic agent used in the treatment of pancreatic cancer, but the mechanisms of gemcitabine sensitivity are still controversial. In our study to determine a mechanism that regulates gemcitabine sensitivity, we carried out molecular analysis on the susceptibility of the pancreatic cancer cells. Using a gemcitabine-sensitive pancreatic cancer cell line KLMI, we established a resistant cell line KLMI-R exhibiting a 20-fold IC50-value (the concentration of gemcitabine causing 50% growth inhibition). Microarray analysis of genes showed specific expression of selenoprotein P, one of the anti-oxidants, in the KLMI-R cell line but not in the KLMI cell line. Administration of selenoprotein P inhibited the gemcitabine-induced cytotoxicity in the pancreatic cell lines. The levels of intracellular reactive oxygen species (ROS) were increased in the KLMI cells by gemcitabine, but selenoprotein P suppressed the gemcitabine-induced ROS levels. Furthermore interferon-gamma suppressed the expression of selenoprotein P mRNA and increased intracellular ROS level, leading to the recovery of the gemcitabine sensitivity in KLMI-R. These results suggest a novel mechanism that selenoprotein P reduces the intracellular ROS levels, resulting in the insusceptibility to gemcitabine. (C) 2004 Wiley-Liss, Inc.