Phosphorylation of the mRNA cap-binding protein eIF4E and cancer.

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.

蛋白质合成失调常常涉及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子。eIF4E的活性在多个层面受到调控，其中之一是通过丝裂原活化蛋白激酶相互作用激酶（MNKs，包括MNK1和MNK2）在丝氨酸209位点对其进行磷酸化。得益于新型小鼠基因工具和MNK的药理学抑制剂，近年来我们对eIF4E磷酸化在肿瘤生物学和癌症治疗中的作用的理解有了很大的进展。重要的是，近期研究发现，在多种人类癌症类型中，eIF4E磷酸化水平常常上调，并且eIF4E的磷酸化驱动了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。在不同的癌症模型中，MNK - eIF4E轴正在被评估为单独的或与其他疗法联合的治疗靶点。随着新型MNK抑制剂的研发，实验研究为治愈对传统疗法无反应的人类癌症带来了新的希望。在此我们综述了近年来在我们对eIF4E磷酸化在癌症生物学和治疗中的机制作用的理解方面的进展。