Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Am J Respir Cell Mol Biol. 2022 Jul;67(1):36-49. doi: 10.1165/rcmb.2021-0428OC.
Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for AURKA (Aurora kinase A), induced YAP phosphorylation and cytoplasmic retention and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2 (Large Tumor Suppressor 1 and 2). Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFβ (Transforming Growth Factor β) signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with antifibrotic activity.
特发性肺纤维化是一种进展性肺部疾病，治疗方法有限，其特征是病理性成纤维细胞激活和异常的肺重塑伴有瘢痕形成。YAP（Yes 相关蛋白）是一种转录共激活因子，可介导控制成纤维细胞激活的机械和生化信号。我们之前基于原代人肺成纤维细胞的高通量小分子筛选，将 HMG-CoA（3-羟基-3-甲基戊二酰辅酶 A）还原酶抑制剂（他汀类药物）鉴定为 YAP 抑制剂。在这里，我们报告说，几种 Aurora 激酶抑制剂也从该筛选的顶级命中中被鉴定出来。MK-5108 是一种高度选择性的 AURKA（Aurora 激酶 A）抑制剂，可诱导 YAP 磷酸化和细胞质保留，并显著降低人肺成纤维细胞中致纤维基因的表达。对 YAP 核易位和致纤维基因表达的抑制作用是对 AURKA 抑制的特异性，而不是 Aurora 激酶 B 或 C，并且独立于 Hippo 通路激酶 LATS1 和 LATS2（大肿瘤抑制物 1 和 2）。对 MK-5108 作用的进一步表征表明，它通过对肌动蛋白聚合和 TGFβ（转化生长因子 β）信号的影响间接抑制 YAP 核定位。此外，MK-5108 治疗可减少博莱霉素诱导的肺纤维化小鼠模型中的肺胶原沉积。我们的结果揭示了 AURKA 在成纤维细胞中 YAP 介导的致纤维活性中的新作用，并强调了小分子筛选用于鉴定具有抗纤维化活性的新型 YAP 抑制剂的潜力。
