Computational analysis of G-protein-coupled receptor kinase family members as potential targets for colorectal cancer therapy

Abstract

Background G-protein-coupled receptor (GPCR) kinases (GRKs) interact with ligand-activated GPCR, causing intracellular phosphorylation and interfering with the intracellular signal transduction associated with the development of cancer. Colorectal cancer (CRC) is a fast-growing disease, and its molecular mechanism involves various regulatory proteins, including kinases. However, the GRK mechanism in CRC has not been explored. Methods We used an integrated computational approach to investigate the potential of GRK family members as targeted proteins in CRC. The GRK expression levels in tumor and normal tissues, colon adenocarcinoma samples, and metastatic colon adenocarcinoma were analyzed using ONCOMINE, GEPIA, and UALCAN, as well as TNM plots. Genetic changes in the GRK family genes were investigated using cBioportal. The prognostic value related to the gene expression of the GRK family was examined using GEPIA and UALCAN. Co-expression analysis of the GRK family was conducted using COXPRESdb. Association analysis of the Gene Ontology, KEGG pathway enrichment, and drug-gene analyses were performed using the over-representation analysis (ORA) in WebGestalt. Results GRK2, GRK3, and GRK5 mRNA levels increased significantly in patients with CRC and metastatic CRC. Genetic changes were detected in patients with CRC, including GRK7 (1.1%), GRK2 (1.7%), GRK4 (2.3%), GRK5 (2.5%), GRK6 (2.5%), GRK3 (2.9%), and GRK1 (4%). CRC patients with low mRNA of GRK7 levels had better disease-free and overall survival than those with high GRK7 levels. Hierarchical clustering analysis revealed significant positive correlations between GRK5 and GRK2 and between GRK2 and GRK6. KEGG pathway enrichment analysis showed that the gene network (GN) regulated several cellular pathways, such as the morphine addiction signaling and chemokine signaling pathways in cancer. The drug-gene association analysis indicated that the GN was associated with several drugs, including reboxetine, pindolol, beta-blocking agents, and protein kinase inhibitors. Conclusion No research has been conducted on the relation of GRK1 and GRK7 to cancer, particularly CRC. In this work, genes GRK2, GRK3, GRK5, and GRK6 were found to be oncogenes in CRC. Although inhibitors against GRK2, GRK5, and GRK6 have previously been developed, further research, particularly preclinical and clinical studies, is needed before these agents may be used to treat CRC.