KRAS Oncoprotein Expression Is Regulated by a Self-Governing eIF5A-PEAK1 Feed-Forward Regulatory Loop.
KRAS Oncoprotein Expression Is Regulated by a Self-Governing eIF5A-PEAK1 Feed-Forward Regulatory Loop.
复制标题
DOI：
10.1158/0008-5472.can-17-2873
复制
发表时间：
2018-03-15
期刊：
影响因子：
11.2
通讯作者：
Klemke RL
中科院分区：
文献类型：
--
作者：
Fujimura K;Wang H;Watson F;Klemke RL
仍然有强烈的兴趣，在易于处理的方法来靶向或沉默的KRAS癌蛋白作为一个合理的治疗策略，以攻击胰腺癌（PDAC）和其他癌症overexpressedit. There我们提供的证据表明，积累的KRAS癌蛋白是由一个自我调节的前馈调节环，利用一个独特的hypusinated异构体的翻译延伸因子eIF 5A和酪氨酸激酶PEAK 1控制。KRAS的致癌激活增加了eIF 5A-PEAK 1翻译信号传导，这反过来又促进了KRAS蛋白合成的增加。机制研究表明，这种前馈正调控途径由致癌KRAS驱动的代谢需求控制，独立于典型的mTOR信号传导，并且不涉及新的KRas基因转录。在已建立的PDAC临床前小鼠模型中，通过遗传或药理学策略或通过阻断谷氨酰胺合成干扰eIF 5A-PEAK 1信号传导足以抑制KRAS、eIF 5A和PEAK 1的表达，减弱癌细胞生长和迁移，并阻断肿瘤形成。KRAS、eIF 5A和PEAK 1蛋白的水平在癌症进展期间增加，在转移性细胞群体中观察到最高水平的表达。eIF 5A hypusination和RAS-ERK信号传导途径的组合靶向协同减弱KRAS表达及其下游信号传导沿着体外细胞生长和体内肿瘤形成。总的来说，我们的研究结果强调了一种新的机制策略，以减弱KRAS表达作为靶向PDAC和其他由KRAS激活驱动的人类癌症的治疗策略。
There remains intense interest in tractable approaches to target or silence the KRAS oncoprotein as a rational therapeutic strategy to attack pancreatic adenocarcinoma (PDAC) and other cancers which overexpress it. Here we provide evidence that accumulation of the KRAS oncoprotein is controlled by a self-regulating feed-forward regulatory loop that utilizes a unique hypusinated isoform of the translation elongation factor eIF5A and the tyrosine kinase PEAK1. Oncogenic activation of KRAS increased eIF5A-PEAK1 translational signaling, which in turn facilitated increased KRAS protein synthesis. Mechanistic investigations shows that this feed-forward positive regulatory pathway was controlled by oncogenic KRAS-driven metabolic demands, operated independently of canonical mTOR signaling, and did not involve new KRas gene transcription. Perturbing eIF5A-PEAK1 signaling, by genetic or pharmacologic strategies or by blocking glutamine synthesis, was sufficient to inhibit expression of KRAS, eIF5A, and PEAK1, attenuate cancer cell growth and migration, and block tumor formation in established preclinical mouse models of PDAC. Levels of KRAS, eIF5A, and PEAK1 protein increased during cancer progression with the highest levels of expression observed in metastatic cell populations. Combinatorial targeting of eIF5A hypusination and the RAS-ERK signaling pathway cooperated to attenuate KRAS expression and its downstream signaling along with cell growth in vitro and tumor formation in vivo. Collectively, our findings highlight a new mechanistic strategy to attenuate KRAS expression as a therapeutic strategy to target PDAC and other human cancers driven by KRAS activation.