Abstract
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.
Highlights
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)
We observed that GRK5 is significantly higher expressed in mesenchymal-like breast cancer cells and that MDA-MB-231 cells, a metastatic, triple-negative breast cancer cell line, showed the highest GRK5 expression level of all analysed cell lines (Fig. 1A)
A breast cancer cell line screen revealed that GRK5 is mainly expressed in triple-negative breast cancer (TNBC) cell lines, which possess a mesenchymal like phenotype and are able to migrate
Summary
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). All GRKs regulate the GPCR signalling by phosphorylating agonist-activated GPCRs in the third cytoplasmic loop and/or the C-terminal tail This leads to the recruitment of β-arrestins and subsequently to the uncoupling of the G proteins. Since 2006 sunitinib is approved by the FDA for the treatment of gastrointestinal stromal tumours, which are refractory or intolerant to imatinib treatment, and for advanced, metastatic renal cell carcinoma (mRCC)[21,22] This multispecific kinase inhibitor was shown to mainly www.nature.com/scientificreports inhibit the receptor tyrosine kinases (RTKs) vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR)[23] thereby blocking the angiogenesis of tumours. We investigated the effect of sunitinib on GRK5 and breast cancer cells in vitro
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
