Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels
Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels
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DOI：
10.1074/jbc.m115.687418
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发表时间：
2015-12-11
影响因子：
4.8
通讯作者：
Klemke, Richard
中科院分区：
文献类型：
--
作者：
Fujimura, Ken;Choi, Sunkyu;Klemke, Richard
胰腺导管腺癌（PDAC）是最致命的癌症之一，总生存率不到5%。PDAC患者预后差主要是由于在诊断时全身性转移的高患病率以及缺乏针对弥散细胞的有效治疗方法。事实上，驱动PDAC细胞迁移和传播的潜在机制尚不清楚，这阻碍了药物开发，并加剧了该疾病临床成功的缺乏。最近的证据表明，K-Ras的突变激活上调了eIF5A，这是细胞翻译机制的一个组成部分，对PDAC的进展至关重要。然而，eIF5A在PDAC细胞迁移和转移中的作用尚未被研究。我们在这里报道，药物抑制或基因敲低eIF5A可减少PDAC细胞在体内和体外的迁移、侵袭和转移。蛋白质组学分析和生物信息学分析显示，eIF5A控制着参与细胞迁移的细胞骨架调节蛋白的集成网络。对该网络的功能研究发现，在侵袭性PDAC细胞中，一个关键的RhoA/ROCK信号节点在eIF5A下游运作。重要的是，eIF5A通过调节RhoA/ROCK蛋白表达水平介导PDAC细胞迁移和侵袭。总之，我们的研究结果表明eIF5A在PDAC细胞迁移和转移过程中作为细胞骨架变阻器控制RhoA/ROCK蛋白的表达。我们的研究结果还暗示eIF5A/RhoA/ROCK模块是治疗转移性PDAC细胞的潜在新治疗靶点。
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with an overall survival rate of less than 5%. The poor patient outcome in PDAC is largely due to the high prevalence of systemic metastasis at the time of diagnosis and lack of effective therapeutics that target disseminated cells. The fact that the underlying mechanisms driving PDAC cell migration and dissemination are poorly understood have hindered drug development and compounded the lack of clinical success in this disease. Recent evidence indicates that mutational activation of K-Ras up-regulates eIF5A, a component of the cellular translational machinery that is critical for PDAC progression. However, the role of eIF5A in PDAC cell migration and metastasis has not been investigated. We report here that pharmacological inhibition or genetic knockdown of eIF5A reduces PDAC cell migration, invasion, and metastasis in vitro and in vivo. Proteomic profiling and bioinformatic analyses revealed that eIF5A controls an integrated network of cytoskeleton-regulatory proteins involved in cell migration. Functional interrogation of this network uncovered a critical RhoA/ROCK signaling node that operates downstream of eIF5A in invasive PDAC cells. Importantly, eIF5A mediates PDAC cell migration and invasion by modulating RhoA/ROCK protein expression levels. Together our findings implicate eIF5A as a cytoskeletal rheostat controlling RhoA/ROCK protein expression during PDAC cell migration and metastasis. Our findings also implicate the eIF5A/RhoA/ROCK module as a potential new therapeutic target to treat metastatic PDAC cells.