Dysregulated protein synthesis is frequently involved in oncogenesis and cancer progression. Translation initiation is thought to be the rate-limiting step in protein synthesis, and the mRNA 5′ cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) is a pivotal factor that initiates translation. The activities of eIF4E are regulated at multiple levels, one of which is through its phosphorylation at Serine 209 by the mitogen-activated protein kinase-interacting kinases (MNKs, including MNK1 and MNK2). Benefiting from novel mouse genetic tools and pharmacological MNK inhibitors, our understanding of a role for eIF4E phosphorylation in tumor biology and cancer therapy has greatly evolved in recent years. Importantly, recent studies have found that the level of eIF4E phosphorylation is frequently upregulated in a wide variety of human cancer types, and phosphorylation of eIF4E drives a number of important processes in cancer biology, including cell transformation, proliferation, apoptosis, metastasis and angiogenesis. The MNK-eIF4E axis is being assessed as a therapeutic target either alone or in combination with other therapies in different cancer models. As novel MNK inhibitors are being developed, experimental studies bring new hope to cure human cancers that are not responsive to traditional therapies. Herein we review recent progress on our understanding of a mechanistic role for phosphorylation of eIF4E in cancer biology and therapy.

蛋白质合成失调经常参与肿瘤发生和癌症进展。翻译起始被认为是蛋白质合成的限速步骤，而 mRNA 5'帽结合蛋白真核翻译起始因子 4E (eIF4E) 是启动翻译的关键因素。 eIF4E 的活性在多个水平上受到调节，其中之一是通过丝裂原激活蛋白激酶相互作用激酶（MNK，包括 MNK1 和 MNK2）对其丝氨酸 209 进行磷酸化。受益于新型小鼠遗传工具和药理学 MNK 抑制剂，近年来我们对 eIF4E 磷酸化在肿瘤生物学和癌症治疗中作用的理解有了很大进展。重要的是，最近的研究发现，eIF4E磷酸化水平在多种人类癌症类型中经常上调，并且eIF4E磷酸化驱动癌症生物学中的许多重要过程，包括细胞转化、增殖、凋亡、转移和血管生成。 MNK-eIF4E 轴正在被评估为单独的治疗靶点或与不同癌症模型中的其他疗法联合使用。随着新型 MNK 抑制剂的开发，实验研究为治愈对传统疗法无效的人类癌症带来了新的希望。在此，我们回顾了对 eIF4E 磷酸化在癌症生物学和治疗中的机制作用的理解的最新进展。