Functional network analysis of gene-phenotype connectivity based on pioglitazone

Pioglitazone, a type of insulin sensitizer, serves as an effective anti-hyperglycemic drug. The mechanism of action of pioglitazone is through the activation of the peroxisome proliferator-activated receptor (PPAR), which results in enhanced insulin sensitivity of peripheral tissues and the liver, causing a reduction in the production and output of liver sugar. It has been reported that pioglitazone increases the risk of bladder cancer, but the underlying mechanisms have remained elusive. It was hypothesized that modulation of pioglitazone activity may be predicted by systematically analyzing data published on drugs. This hypothesis was tested by querying the Drug-Target Interactome (DTome), a web-based tool that provides open-source data from three databases (DrugBank, PharmGSK and Protein Interaction Network analysis). A total of 4 direct target proteins (DTPs) and further DTP-associated genes were identified for pioglitazone. Subsequently, an enrichment analysis was performed for all DTP-associated genes using Cytoscape software. A total of 12 Kyoto Encyclopedia of Genes and Genomes pathways were identified, including the ‘PPAR signaling pathway’ as well as ‘pathways in cancer’ as relevant pathways. Functional network analysis was able to identify direct and indirect target genes of pioglitazone, resulting in a list of possible biological functions based on published databases. Furthermore, Kaplan-Meier analysis indicated that pioglitazone may affect the survival rate of patients with bladder cancer through genetic alterations (missense mutation, truncating mutation, amplification, deep deletion and fusion) of target genes. Therefore, it should be used with caution.