Eukaryotic translation initiation factor 4E (eIF4E) is deregulated in patients with renal cell carcinoma (RCC) and associated with poor prognosis, and is activated and regulated by Mnk kinases. In this study, we investigated the anti-RCC potential of a unique Mnk inhibitor cercosporamide. We showed that cercosporamide is active against RCC cells via suppressing growth, survival and migration. Combination indices value indicated that the combination of cercosporamide with sunitinib or temsirolimus are synergistic in RCC. In two independent RCC xenograft mouse models, complete tumor growth arrest or reverse was observed throughout the duration of drug treatment in the combination of cercosporamide with sunitinib or temsirolimus groups. Of note, cercosporamide inhibited RCC angiogenesis via negatively regulating a number of RCC endothelial cellular events including morphogenesis, migration, growth and survival. Mechanistically, we found that cercosporamide suppressed pro-angiogenic factors VEGF and HIFα, inhibited EMT and reduced pro-survival and cell cycle proteins; and furthermore this was attributed to cercosporamide’s ability in inhibiting eIF4E. This work demonstrates the anti-RCC activity of cercosporamide through targeting both RCC tumor cells and angiogenesis, and provides the first preclinical proof-of-concept of evidence of Mnk inhibition for RCC treatment.

真核翻译起始因子4E（eIF4E）在肾细胞癌（RCC）患者中被解除调节且预后不良，并被Mnk激酶激活和调节。在这项研究中，我们研究了独特的Mnk抑制剂cercosporamide的抗RCC潜力。我们表明，cercosporamide通过抑制生长，存活和迁移对RCC细胞具有活性。组合指数值表明，cercosporamide与舒尼替尼或替西罗莫司的组合在RCC中具有协同作用。在两个独立的RCC异种移植小鼠模型中，在头孢菌酰胺与舒尼替尼或西罗莫司组的组合药物治疗期间，观察到肿瘤生长完全停止或逆转。值得注意的是 cercosporamide通过负向调节许多RCC内皮细胞事件（包括形态发生，迁移，生长和存活）来抑制RCC血管生成。从机理上讲，我们发现cercosporamide抑制促血管生成因子VEGF和HIFα，抑制EMT并降低促生存和细胞周期蛋白。而且这归因于cercosporamide抑制eIF4E的能力。这项工作通过针对RCC肿瘤细胞和血管生成证明了cercosporamide的抗RCC活性，并提供了Mcc抑制RCC治疗的证据的首个临床前概念证据。而且这归因于cercosporamide抑制eIF4E的能力。这项工作通过针对RCC肿瘤细胞和血管生成证明了cercosporamide的抗RCC活性，并提供了Mcc抑制RCC治疗的证据的首个临床前概念证据。而且这归因于cercosporamide抑制eIF4E的能力。这项工作通过针对RCC肿瘤细胞和血管生成证明了cercosporamide的抗RCC活性，并提供了Mcc抑制RCC治疗的证据的首个临床前概念证据。