ABSTRACT

The mitogen-activated protein kinase kinase 5 (MEK5)/extracellular signal-regulated kinase 5 (ERK5) axis has been reported to promote tumorigenesis in breast cancer (BC). Therefore, targeting the MEK5/ERK5 axis is a potential strategy against BC. BAY-885 is a novel inhibitor of ERK5; however, to date, its anti-tumor effects in BC have not been investigated. This study aimed to assess the anti-tumor effects of BAY-885 in BC and identify its underlying mechanisms of action. Unlike other ERK5 inhibitors, which frequently failed to mimic ERK5 genetic ablation phenotypes, the BAY-885 treatment effectively recapitulated ERK5 depletion effects in BC cells. Results revealed that BAY-885 affected the viability and induced apoptosis in BC cells. Moreover, the BAY-885-mediated downregulation of myeloid cell leukemia-1 (Mcl-1) and upregulation of Bim were dependent on ERK5 inhibition. Furthermore, BAY-885 triggered activation of endoplasmic reticulum (ER) stress, which further led to the upregulation of Bim and downregulation of Mcl-1. ER stress was induced in an ERK5 inhibition-dependent manner. These findings suggested that BAY-885 induced apoptosis in BC cells via ER stress/Mcl-1/Bim axis, suggesting that BAY-885 may serve as a therapeutic agent for BC.

 抽象的

据报道，丝裂原激活蛋白激酶激酶 5 (MEK5)/细胞外信号调节激酶 5 (ERK5) 轴可促进乳腺癌 (BC) 的肿瘤发生。因此，针对 MEK5/ERK5 轴是对抗 BC 的潜在策略。 BAY-885是一种新型ERK5抑制剂；然而，迄今为止，其在 BC 中的抗肿瘤作用尚未得到研究。本研究旨在评估 BAY-885 在 BC 中的抗肿瘤作用并确定其潜在作用机制。与其他经常无法模拟 ERK5 基因消融表型的 ERK5 抑制剂不同，BAY-885 治疗有效地重现了 BC 细胞中的 ERK5 耗竭效应。结果显示 BAY-885 影响 BC 细胞的活力并诱导细胞凋亡。此外，BAY-885 介导的髓样细胞白血病-1 (Mcl-1) 下调和 Bim 上调依赖于 ERK5 抑制。此外，BAY-885 触发内质网 (ER) 应激激活，进一步导致 Bim 上调和 Mcl-1 下调。 ER 应激以 ERK5 抑制依赖性方式诱导。这些发现表明，BAY-885 通过 ER 应激/Mcl-1/Bim 轴诱导 BC 细胞凋亡，表明 BAY-885 可作为 BC 的治疗剂。