The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1.
The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1.
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原癌基因 c-Src 及其下游信号通路受到转移抑制因子 NDRG1 的抑制。
DOI：
10.18632/oncotarget.3316
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发表时间：
2015-04-20
期刊：
影响因子：
--
通讯作者：
Richardson DR
中科院分区：
文献类型：
--
作者：
Liu W;Yue F;Zheng M;Merlot A;Bae DH;Huang M;Lane D;Jansson P;Lui GY;Richardson V;Sahni S;Kalinowski D;Kovacevic Z;Richardson DR
N-myc下游调节基因-1（NDRG 1）是一种有效的转移抑制基因，在调节参与介导癌细胞侵袭和迁移的信号通路中起关键作用，包括来自前列腺、结肠等的癌细胞。然而，NDRG 1通过其降低癌细胞侵袭和迁移，从而抑制癌症转移的机制和分子靶点尚未完全阐明。在这项研究中，使用NDRG 1在三种肿瘤细胞类型（即DU 145，PC 3 MM和HT 29）中的过表达模型以及DU 145和HT 29细胞中的NDRG 1沉默，我们揭示了NDRG 1降低了关键原癌基因细胞Src（c-Src）在一个充分表征的激活位点（Tyr 416）的磷酸化。NDRG 1介导的EGFR表达和活化的下调是c-Src（Tyr 416）磷酸化减少的原因。事实上，NDRG 1阻止了c-Src向EGFR的募集和c-Src活化。此外，NDRG 1通过调节c-Src下游效应物p130 Cas的磷酸化及其与CrkII的结合来抑制Rac 1活性，CrkII作为激活Rac 1的“分子开关”。NDRG 1还影响另一种参与调节Rac 1信号传导的信号分子c-Abl，c-Abl随后抑制CrkII磷酸化。相对于对照，NDRG 1沉默增加了细胞迁移，并且使用siRNA或药理学抑制剂（SU 6656）抑制c-Src信号传导防止了这种增加。因此，NDRG 1在减少细胞迁移中的作用部分是由于其抑制c-Src活化。此外，新的药理学药物，诱导NDRG 1的表达，目前正在开发的抗转移剂，显着增加NDRG 1和减少c-Src激活。这项研究对NDRG 1抑制转移的机制以及如何用新的治疗方法靶向这些途径提供了重要的见解。
N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that plays a key role in regulating signaling pathways involved in mediating cancer cell invasion and migration, including those derived from prostate, colon, etc. However, the mechanisms and molecular targets through which NDRG1 reduces cancer cell invasion and migration, leading to inhibition of cancer metastasis, are not fully elucidated. In this investigation, using NDRG1 over-expression models in three tumor cell-types (namely, DU145, PC3MM and HT29) and also NDRG1 silencing in DU145 and HT29 cells, we reveal that NDRG1 decreases phosphorylation of a key proto-oncogene, cellular Src (c-Src), at a well-characterized activating site (Tyr416). NDRG1-mediated down-regulation of EGFR expression and activation were responsible for the decreased phosphorylation of c-Src (Tyr416). Indeed, NDRG1 prevented recruitment of c-Src to EGFR and c-Src activation. Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a “molecular switch” to activate Rac1. NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, c-Abl, which then inhibited CrkII phosphorylation. Silencing NDRG1 increased cell migration relative to the control and inhibition of c-Src signaling using siRNA, or a pharmacological inhibitor (SU6656), prevented this increase. Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation. In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation. This study leads to important insights into the mechanism involved in inhibiting metastasis by NDRG1 and how to target these pathways with novel therapeutics.
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影响因子：
5.3
作者：
Coniglio, Salvatore J.;Zavarella, Salvatore;Symons, Marc H.
通讯作者：
Symons, Marc H.
影响因子：
4
作者：
Jin, Runsen;Liu, Wensheng;Richardson, Des R.
通讯作者：
Richardson, Des R.
影响因子：
4.8
作者：
Gutierrez, Elaine;Richardson, Des R.;Jansson, Patric J.
通讯作者：
Jansson, Patric J.
影响因子：
8.8
作者：
Dixon, K. M.;Lui, G. Y. L.;Kovacevic, Z.;Zhang, D.;Yao, M.;Chen, Z.;Dong, Q.;Assinder, S. J.;Richardson, D. R.
通讯作者：
Richardson, D. R.
DOI：
10.1016/j.bbapap.2007.08.012
发表时间：
2008-01-01
影响因子：
3.2
作者：
Ingley, Evan
通讯作者：
Ingley, Evan