Peroxiredoxin I plays a protective role against cisplatin cytotoxicity through mitogen activated kinase signals.
Peroxiredoxin I plays a protective role against cisplatin cytotoxicity through mitogen activated kinase signals.
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DOI：
10.1016/j.oraloncology.2009.07.002
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发表时间：
2009-12
期刊：
影响因子：
4.8
通讯作者：
Dongmei Ma;E. Warabi;T. Yanagawa;Shintaro Kimura;Harumi Harada;K. Yamagata;T. Ishii
中科院分区：
文献类型：
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作者：
Dongmei Ma;E. Warabi;T. Yanagawa;Shintaro Kimura;Harumi Harada;K. Yamagata;T. Ishii
抗癌剂顺二氨二氯铂（顺铂）是口腔癌的一线化疗药物。细胞暴露于顺铂与氧化应激增加和细胞凋亡途径组分的翻译后变化相关，包括p38促分裂原活化蛋白激酶（MAPK）、c-Jun-NH 2-激酶（JNK）和细胞外信号调节激酶（ERK）。Peroxiredoxin（Prx）I是一种氧化应激诱导蛋白，在许多组织中表达，对于减少体内活性氧自由基很重要;然而，Prx I是否有助于保护细胞免受顺铂损伤尚不清楚。在这份报告中，我们研究了Prx I对顺铂诱导的细胞凋亡的敏感性的影响。来自Prx I缺陷小鼠的小鼠胚胎成纤维细胞（MEFs）与野生型MEFs相比，顺铂诱导的凋亡增加。顺铂治疗也导致增加激活p38 MAPK和JNK，并减少ERK磷酸化在Prx I缺陷的MEFs相比，野生型MEFs。此外，JNK和ERK特异性抑制剂保护Prx I缺陷MEFs免受顺铂诱导的凋亡，但Prx I缺陷MEFs在用p38 MAPK特异性抑制剂处理时仍比野生型MEFs更敏感。这些研究结果表明，Prx I调节顺铂诱发的MAPK激活，导致细胞凋亡，因此Prx I可能是一个有用的目标，作为对顺铂细胞毒性的保护性治疗。
The anticancer agent cis-diamminedichloroplatinum (cisplatin) is a first-line chemotherapeutic agent for oral cancer. Cell exposure to cisplatin is associated with increased oxidative stress and post-translational changes in components of apoptosis pathways, including p38 Mitogen-activated protein kinase (MAPK), c-Jun-NH2-kinase (JNK), and extracellular signal-regulated kinase (ERK). Peroxiredoxin (Prx) I is an oxidative stress-inducible protein expressed in many tissues and important for reducing reactive oxygen species in vivo; however, whether Prx I helps protect cells from cisplatin injury is unknown. In this report, we examined the effects of Prx I on cell sensitivity to cisplatin-induced apoptosis. Mouse embryo fibroblasts (MEFs) derived from Prx I-deficient mice showed increased cisplatin-induced apoptosis compared with wild-type MEFs. Cisplatin treatment also led to increased activation of p38 MAPK and JNK, and reduced ERK phosphorylation in Prx I-deficient MEFs compared with wild-type MEFs. Furthermore, JNK- and ERK-specific inhibitors protected the Prx I-deficient MEFs from cisplatin-induced apoptosis, but Prx I-deficient MEFs remained more sensitive than wild-type MEFs when treated with a p38 MAPK-specific inhibitor. These findings indicate that Prx I modulates the cisplatin-evoked activation of MAPKs that lead to apoptosis, and Prx I may thus represent a useful target as a protective therapy against cisplatin cytotoxicity.