Use of integrative bioinformatics to identify targets of sinensetin and its mechanisms to overcome colorectal cancer resistance

It was previously shown that sinensetin increases the effectiveness of 5-fluorouracil (5-FU) in spheroids derived from colorectal cancer (CRC) cells; however, the molecular mechanism by which this occurs remains elusive. This study aims to explore the targets of sinensetin and the molecular mechanisms by which it circumvents CRC resistance. Targets of sinensetin were obtained from the SwissTargetPrediction platform, while regulatory genes of human CRC cells were downloaded from the PubMed database. Venn diagram resulted in 36 potential therapeutic targets of sinensetin against chemoresistance in CRC potential therapeutic target genes of sinensetin (PS). Analyses of gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were conducted with WebGestalt and Database for Annotation, Visualization, and Integrated Discovery, respectively. Protein–protein interaction network and hub gene selection were analyzed by STRING and CytoHubba. Analysis of genetic alterations of PS was carried out using cBioPortal. The analytical results of KEGG pathway enrichment revealed that the CRC and vascular endothelial growth factor signaling pathways, the erbB signaling pathway, and ATP-binding cassette transporters are altered in PS. Moreover, genetic alterations of the query genes affected several pathways, including COADREAD-2012-RTK-RAS-PI(3)K, which regulates proliferation, cell survival, and translation. Sinensetin potentially targets ATP-binding cassette sub-family G member 2, ATP-binding cassette sub-family B member 1, B-Raf proto-oncogene, serine/threonine kinase, MET, platelet-derived growth factor receptor beta, Glycogen synthase kinase-3 beta, and hosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform. Moreover, the phosphatidylinositide 3-OH kinase/AKT serine/threonine kinase and mitogen-activated protein kinase signaling pathways are potential target pathways of sinensetin action. The results of the present study await validation by subsequent experiments. © 2021. Hermawan and Putri.