Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours
Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours
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DOI：
10.1038/onc.2017.93
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发表时间：
2017-08-17
期刊：
影响因子：
8
通讯作者：
Rajalingam, K.
中科院分区：
文献类型：
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作者：
Yurugi, H.;Marini, F.;Rajalingam, K.
KRAS是人类非小细胞肺癌(NSCLC)中最常见的突变癌基因之一。RAS蛋白可激活多种效应信号通路，包括高度保守的RAF-MAPK通路。CRAF是一种直接的RAS效应蛋白，在KRAS介导的肿瘤发生中是必需的。因此，对CRAF激活的分子机制进行了深入的研究。Prohibitin 1(PHB1)是一种进化上保守的适配蛋白，CRAF与PHB1在质膜上的相互作用是CRAF激活的关键。在这里，我们证明了PHB1在非小细胞肺癌患者中高表达，并与低存活率相关。靶向PHB1的两种化学配体(洛格列胺和氟唑啉)可抑制表皮生长因子(EGF)/RAS诱导的CRAF激活。一直以来，洛格拉胺治疗抑制了KRAS突变的肺癌细胞系的增殖、迁移和非锚定生长。令人惊讶的是，罗格列胺处理抑制了KRAS突变细胞和EGF刺激的细胞中的RAS-GTP负荷。罗格拉胺治疗进一步阻止了KRAS驱动的同种和异种肺癌移植物在小鼠模型中的致癌生长。我们的结果表明，罗格列胺作为RAS抑制剂，用化学配体靶向质膜相关的PHB1将是对抗KRAS介导的NSCLC的一种可行的治疗策略。
KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancers (NSCLCs). RAS proteins trigger multiple effector signalling pathways including the highly conserved RAF-MAPK pathway. CRAF, a direct RAS effector protein, is required for KRAS-mediated tumourigenesis. Thus, the molecular mechanisms driving the activation of CRAF are intensively studied. Prohibitin 1 (PHB1) is an evolutionarily conserved adaptor protein and interaction of CRAF with PHB1 at the plasma membrane is essential for CRAF activation. Here, we demonstrate that PHB1 is highly expressed in NSCLC patients and correlates with poor survival. Targeting of PHB1 with two chemical ligands (rocaglamide and fluorizoline) inhibits epidermal growth factor (EGF)/RAS-induced CRAF activation. Consistently, treatment with rocaglamide inhibited proliferation, migration and anchorage-independent growth of KRAS-mutated lung carcinoma cell lines. Surprisingly, rocaglamide treatment inhibited Ras-GTP loading in KRAS-mutated cells as well as in EGF-stimulated cells. Rocaglamide treatment further prevented the oncogenic growth of KRAS-driven lung cancer allografts and xenografts in mouse models. Our results suggest rocaglamide as a RAS inhibitor and that targeting plasma membrane-associated PHB1 with chemical ligands would be a viable therapeutic strategy to combat KRAS-mediated NSCLCs.