ERK1/2 is highly phosphorylated in melanoma metastases and protects melanoma cells from cisplatin-mediated apoptosis
ERK1/2 is highly phosphorylated in melanoma metastases and protects melanoma cells from cisplatin-mediated apoptosis
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DOI：
10.1038/sj.jid.5700870
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发表时间：
2007-09-01
影响因子：
6.5
通讯作者：
Hengge, Ulrich R.
中科院分区：
文献类型：
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作者：
Mirmohammadsadegh, Alireza;Mota, Rodrigo;Hengge, Ulrich R.
通过BRAF和RAS激活（磷酸化）丝裂原活化蛋白激酶（MAPK）信号转导可引起包括细胞存活和细胞死亡在内的多种功能影响。在这项研究中，我们在临床黑色素瘤转移和各种黑色素瘤细胞系中观察到高细胞外信号调节激酶（ERK）1/2磷酸化水平。顺铂是一种有效的抗肿瘤药物，用顺铂治疗黑色素瘤细胞系可增加磷酸化erk (P-ERK)1/2的水平，并通过激活细胞存活蛋白90kda核糖体S6激酶（RSK）1增强化疗耐药。有丝分裂原活化蛋白激酶激酶（MEK）抑制剂（U0126）能够阻断这种作用，降低细胞活力，使细胞对顺铂相关的凋亡敏感，PARP切割、caspase 3表达和annexin-V染色显示。综上所述，MAP激酶- erk通路在黑色素瘤中被激活，降低了黑色素瘤对顺铂的敏感性。因此，抑制ERK1/2与选定的化疗药物联合使用可能会更有效地治疗黑色素瘤。
Activation (phosphorylation) of mitogen -activated protein kinase (MAPK) signal transduction through BRAF and RAS causes a variety of functional effects including cell survival and cell death. In this study, we observed high extracellular signal-regulated kinase (ERK)1/2 phosphorylation levels in clinical melanoma metastases and various melanoma cell lines. Treatment of melanoma cell lines with cisplatin, a potent antitumor agent, increased the level of phosphorylated-ERK (P-ERK)1/2 and enhanced chemoresistance through activation of the cell survival protein 90-kDa ribosomal S6 kinase (RSK)1. The mitogen -activated protein kinase kinase (MEK) inhibitor (U0126) was able to block this effect and reduced cell viability and sensitized cells to cisplatin-incluced apoptosis, as shown by PARP cleavage, caspase 3 expression, and annexin-V staining. In conclusion, the MAP kinase-ERK pathway is activated in melanoma and reduces the sensitivity of melanoma to cisplatin. Thus, inhibition of ERK1/2 in combination with selected chemotherapeutic agents may hold promise for more effective therapy of melanoma.