High level of mitogen-activated protein kinase phosphatase-1 expression is associated with cisplatin resistance in osteosarcoma.
High level of mitogen-activated protein kinase phosphatase-1 expression is associated with cisplatin resistance in osteosarcoma.
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DOI：
10.1002/pbc.21727
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发表时间：
2008-12
影响因子：
3.2
通讯作者：
Ravindranath Y
中科院分区：
文献类型：
--
作者：
Wang Z;Zhou JY;Kanakapalli D;Buck S;Wu GS;Ravindranath Y
顺铂是治疗包括骨肉瘤（OS）在内的多种实体瘤最有效的化疗药物之一。尽管进行了积极的治疗，但仍有25%的OS患者死于疾病。由于基于顺铂的方案已统一用于OS治疗，因此治疗失败可能至少部分归因于顺铂耐药。本研究的目的是确定MKP-1表达与骨肉瘤细胞系顺铂敏感性之间的关系，并探讨这种关系的机制。检测三种OS细胞系的MKP-1表达和顺铂敏感性。还测量JNK磷酸化和凋亡诱导。采用Western和北方印迹、流式细胞术、siRNA和MTT测定。表达高水平MKP-1的U2 OS细胞对顺铂诱导的细胞死亡不太敏感。通过siRNA沉默抑制MKP-1使U2 OS细胞对顺铂诱导的细胞死亡敏感。此外，在U2 OS中观察到顺铂治疗后延迟的凋亡诱导，与JNK活化降低、MKP-1表达增加和顺铂耐药相对增加平行。有趣的是，MKP-1抑制剂雷公藤内酯醇可阻断MKP-1的表达并增强顺铂诱导的细胞死亡。MKP-1高表达与OS细胞系对顺铂诱导的细胞死亡的敏感性降低或抗性增加相关，MKP-1可能用作顺铂抗性的标志物和分子治疗的治疗靶点。
Cisplatin is one of the most effective chemotherapeutic agents in the treatment of several solid tumors including osteosarcoma (OS). Despite aggressive treatment, 25% of patients with OS continue to die from their disease. Since cisplatin based regimens have been uniformly used in OS therapy, treatment failure is likely due, at least in part, to cisplatin resistance. The objective of this study was to determine the relationship between MKP-1 expression and cisplatin sensitivity of osteosarcoma cell lines and to explore the mechanism underlying this relationship. Three OS cell lines were examined for their MKP-1 expression and cisplatin sensitivity. JNK phosphorylation and apoptosis induction was also measured. Western and Northern blot, flow cytometry, siRNA and MTT assays were used. U2OS cells, which express high level of MKP-1, are less sensitive to cisplatin-induced cell death. Inhibition of MKP-1 by siRNA silencing sensitizes U2OS cells to cisplatin-induced cell death. Furthermore, delayed apoptosis induction following cisplatin treatment was observed in U2OS, in parallel to decreased JNK activation, increased MKP-1 expression and relatively increased cisplatin resistance. Interestingly, triptolide, an MKP-1 inhibitor, blocks MKP-1 expression and enhances cisplatin-induced cell death. High MKP-1 expression is associated with decreased sensitivity or increased resistance to cisplatin-induced cell death in OS cell lines, and MKP-1 could potentially be used as a marker of cisplatin resistance and a therapeutic target for molecular therapies.
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影响因子：
8
作者：
Losa, JH;Cobo, CP;Sánchez-Prieto, R
通讯作者：
Sánchez-Prieto, R
影响因子：
11.2
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11.2
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45.3
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通讯作者：
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影响因子：
8.4
作者：
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通讯作者：
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