Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells
Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells
复制标题
DOI：
10.1038/onc.2010.240
复制
发表时间：
2010-09-01
期刊：
影响因子：
8
通讯作者：
Huang, Y.
中科院分区：
文献类型：
--
作者：
Gan, Y.;Shi, C.;Huang, Y.
表皮生长因子受体（EGFR）的上调和随后的细胞外调节激酶（ERK）和Akt信号转导的增加与前列腺癌进展有关。EGFR的内吞下调受损也有助于致癌表型，如转移。因此，了解不同的信号通路在调节EGFR运输和EGFR驱动的侵袭性迁移中的作用可能有助于开发更有效的治疗方法。在这项研究中，我们使用人前列腺癌细胞系DU 145和PC 3，研究ERK和Akt通路对表皮生长因子（EGF）介导的EGFR信号转导，运输和细胞运动的影响。我们发现DU 145和PC 3细胞过度表达EGFR，并以配体（EGF）依赖的方式迁移。接下来，我们表明，药理学抑制ERK（而不是Akt）信号增强EGF诱导的EGFR激活，泛素化和下调，并可能导致增强受体周转。这些发现与ERK介导的EGFR苏氨酸磷酸化呈负相关，暗示其为可能的机制。此外，我们发现EGF促进细胞-细胞连接的分解，下调E-钙粘蛋白和上调转录抑制因子Snail，这是上皮-间充质转化（EMT）的典型特征。这些作用依赖于Akt的活化，因为Akt信号传导的抑制消除了EGF/EGFR驱动的细胞迁移和EMT。内源性Snail的敲除还防止EGFR介导的E-钙粘蛋白、EMT和细胞迁移的下调。令人惊讶的是，ERK途径的抑制增强了EGFR依赖的运动性，伴随着EGF诱导的Akt活性的升高而发生。总的来说，我们的研究结果表明，表皮生长因子触发的ERK激活有深刻的反馈EGFR信号和贩运的EGFR苏氨酸磷酸化，和Akt有一个关键的作用，EGFR介导的细胞迁移激活EMT。更重要的是，我们的研究结果还表明，治疗靶向ERK信号可能有不良后果（例如，增强EGFR驱动的运动性）。Oncogene（2010）29，4947-4958; doi：10.1038/onc.2010.240; 2010年6月21日在线发表
Upregulation of epidermal growth factor receptor (EGFR) and subsequent increases in extracellular-regulated kinase (ERK) and Akt signaling are implicated in prostate cancer progression. Impaired endocytic downregulation of EGFR also contributes to oncogenic phenotypes such as metastasis. Thus, understanding the roles of divergent signaling pathways in the regulation of EGFR trafficking and EGFR-driven invasive migration may enable the development of more effective therapies. In this study, we use the human prostate cancer cell lines, DU145 and PC3, to investigate the effects of both the ERK and Akt pathways on epidermal growth factor (EGF)-mediated EGFR signaling, trafficking and cell motility. We show that DU145 and PC3 cells overexpress EGFR and migrate in a ligand (EGF)dependent manner. Next, we show that pharmacological inhibition of ERK (but not Akt) signaling enhances EGF-induced EGFR activation, ubiquitination and downregulation, and may lead to enhanced receptor turnover. These findings negatively correlate with ERK-mediated threonine phosphorylation of EGFR, implicating it as a possible mechanism. Further, we uncover that EGF promotes disassembly of cell-cell junctions, downregulation of E-cadherin and upregulation of the transcriptional repressor, Snail, typical characteristics of epithelial-mesenchymal transition (EMT). These effects are dependent on activation of Akt, as inhibition of Akt signaling abolishes EGF/EGFR-driven cell migration and EMT. Knockdown of endogenous Snail also prevents EGFR-mediated downregulation of E-cadherin, EMT and cell migration. Surprisingly, inhibition of the ERK pathway augments EGFR-dependent motility, occurring concomitantly with elevation of EGF-induced Akt activity. Collectively, our results suggest that EGF-triggered ERK activation has profound feedback on EGFR signaling and trafficking by EGFR threonine phosphorylation, and Akt has a pivotal role in EGFR-mediated cell migration by activating EMT. More important, our results also suggest that therapeutic targeting of ERK signaling may have undesirable outcomes (for example, augmenting EGFR-driven motility). Oncogene (2010) 29, 4947-4958; doi: 10.1038/onc.2010.240; published online 21 June 2010