Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, D-81377, Munich, Germany.
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, D-82152, Planegg, Germany.
Sci Rep. 2019 Oct 29;9(1):15548. doi: 10.1038/s41598-019-51923-1.
Sunitinib is a multispecific kinase inhibitor and one of its targets is the kinase GRK5, which is regulating a multitude of G protein-coupled receptors (GPCRs). In this study we demonstrate that a decreased GRK5 expression induced by knock-down experiments or sunitinib treatment hampers the migration of cancer cell lines. A proteomic analysis revealed many pathways related to cell migration which were down regulated upon the GRK5 knock-down. Furthermore, we found in MDA-MB-231 breast cancer cells that the inhibition of migration is mediated by the GPCR gastrin releasing peptide receptor (GRPR) leading to a reduced expression of migration regulating downstream targets like CDC42 and ROCK1. An in silico Kaplan Meier analysis revealed that GRK5 and GRPR overexpression reduces the distant metastasis free survival in triple-negative breast cancer (TNBC) patients. Thus, we suggest a novel anti-migratory effect of impaired GRK5 expression which induces a negative feedback loop on GRPR signalling.
舒尼替尼是一种多靶点激酶抑制剂，其作用靶点之一是激酶 GRK5，它调节多种 G 蛋白偶联受体（GPCR）。在这项研究中，我们证明通过敲低实验或舒尼替尼处理诱导的 GRK5 表达降低会阻碍癌细胞系的迁移。蛋白质组学分析显示，许多与细胞迁移相关的途径在 GRK5 敲低后下调。此外，我们在 MDA-MB-231 乳腺癌细胞中发现，迁移抑制是由 GPCR 胃泌素释放肽受体（GRPR）介导的，导致迁移调节下游靶标如 CDC42 和 ROCK1 的表达减少。计算机 Kaplan-Meier 分析显示，GRK5 和 GRPR 的过表达降低了三阴性乳腺癌（TNBC）患者的远处转移无复发生存率。因此，我们提出了一种新的 GRK5 表达受损的抗迁移作用机制，该作用机制诱导了 GRPR 信号的负反馈环。
