Dysregulation of the mitogen-activated protein kinase interacting kinases 1/2 (MNK1/2)–eukaryotic initiation factor 4E (eIF4E) signaling axis promotes breast cancer progression. MNK1 is known to influence cancer stem cells (CSCs); self-renewing populations that support metastasis, recurrence, and chemotherapeutic resistance, making them a clinically relevant target. The precise function of MNK1 in regulating CSCs, however, remains unexplored. Here, we generated MNK1 knockout cancer cell lines, resulting in diminished CSC properties in vitro and slowed tumor growth in vivo. Using a multiomics approach, we functionally demonstrated that loss of MNK1 restricts tumor cell metabolic adaptation by reducing glycolysis and increasing dependence on oxidative phosphorylation. Furthermore, MNK1-null breast and pancreatic tumor cells demonstrated suppressed metastasis to the liver, but not the lung. Analysis of The Cancer Genome Atlas (TCGA) data from breast cancer patients validated the positive correlation between MNK1 and glycolytic enzyme protein expression. This study defines metabolic perturbations as a previously unknown consequence of targeting MNK1/2, which may be therapeutically exploited.

中文翻译：

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阻断肿瘤内源性 MNK1 激酶可限制代谢适应并减少肝转移


丝裂原活化蛋白激酶相互作用激酶 1/2 （MNK1/2）-真核起始因子 4E （eIF4E） 信号轴的失调促进乳腺癌进展。已知 MNK1 会影响癌症干细胞 （CSC）;支持转移、复发和化疗耐药性的自我更新人群，使其成为临床相关靶标。然而，MNK1 在调节 CSC 中的确切功能仍未得到探索。在这里，我们生成了 MNK1 敲除癌细胞系，导致体外 CSC 特性降低并减缓体内肿瘤生长。使用多组学方法，我们在功能上证明 MNK1 的缺失通过减少糖酵解和增加对氧化磷酸化的依赖性来限制肿瘤细胞代谢适应。此外，MNK1 缺失的乳腺和胰腺肿瘤细胞表现出向肝脏转移的抑制，但未向肺转移。对乳腺癌患者的癌症基因组图谱 （TCGA） 数据的分析验证了 MNK1 与糖酵解酶蛋白表达之间的正相关关系。本研究将代谢扰动定义为靶向 MNK1/2 的先前未知后果，可能被用于治疗。