Extracellular signal-regulated kinase positively regulates the oncogenic activity of MCT-1 in diffuse large B-cell lymphoma.
Extracellular signal-regulated kinase positively regulates the oncogenic activity of MCT-1 in diffuse large B-cell lymphoma.
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DOI：
10.1158/0008-5472.can-09-1606
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发表时间：
2009-10-01
期刊：
影响因子：
11.2
通讯作者：
Gartenhaus RB
中科院分区：
文献类型：
--
作者：
Dai B;Zhao XF;Hagner P;Shapiro P;Mazan-Mamczarz K;Zhao S;Natkunam Y;Gartenhaus RB
MCT-1癌基因最初是从淋巴瘤细胞系中鉴定出来的。在此，我们证实MCT-1在85%的人弥漫性大b细胞淋巴瘤（DLBCL）中高表达，并且在DLBCL细胞中通过特异性短发卡RNA敲低MCT-1可诱导细胞凋亡，支持MCT-1在DLBCL细胞存活中的关键作用。然而，MCT-1调控的机制在很大程度上是未知的。我们发现MCT-1被细胞外信号调节激酶（ERK）磷酸化并上调。此外，通过使用靶向ERK的小抑制分子，我们中断了MCT-1的磷酸化和稳定性。值得注意的是，具有不同水平MCT-1蛋白的细胞对ERK抑制剂诱导的凋亡表现出不同的敏感性。ERK抑制剂在人DLBCL异种移植模型中显示出明显的体内抗肿瘤活性。我们的研究结果建立了MCT-1与MEK/ERK信号通路之间的功能性分子相互作用，并表明MCT-1的上游激酶ERK激活功能在淋巴瘤发生中起重要作用。
The MCT-1 oncogene was originally identified from lymphoma cell lines. Herein we establish that MCT-1 is highly expressed in 85% of human diffuse large B-cell lymphomas (DLBCL) and that knocking down MCT-1 by a specific short hairpin RNA in DLBCL cells induces apoptosis, supporting a critical role for MCT-1 in DLBCL cell survival. However, the mechanism underlying MCT-1 regulation is largely unknown. We find that MCT-1 is phosphorylated and up-regulated by extracellular signal-regulated kinase (ERK). Furthermore, by using a small inhibitory molecule targeting ERK, we interrupted MCT-1 phosphorylation and stability. Significantly, cells with distinct levels of MCT-1 protein displayed differential sensitivity to ERK inhibitor–induced apoptosis. Treatment with the ERK inhibitor showed marked in vivo antitumor activity in a human DLBCL xenograft model. Our findings establish a functional molecular interaction between MCT-1 and the MEK/ERK signaling pathway and suggest that the activation of MCT-1 function by its upstream kinase ERK plays an important role in lymphomagenesis.