Reconstruction and analysis of a signal transduction network using HeLa cell protein–protein interaction data

• Reconstruct a HeLa cell-specific signal transduction network.
• Analyze the reconstructed network and show that at least five proteins have to be inhibited simultaneously for achieving the goals of drug interventions.
• Suggest that a combination drug treatment may be more efficacious than a single-drug approach.

Cancer is a complex disease that is strongly associated with defects in signal transduction pathways. A systematic understanding of signal transduction networks in cancer cells will make it possible to develop alternative therapeutic strategies. However, this understanding relies, at least in part, on the detection of endogenous protein–protein interactions (PPIs) that participate in these networks. The aim of this study is to find intervention strategies under the assumptions of inhibiting cell proliferation and activating cell apoptosis. We utilized 115 endogenous HeLa cell PPIs validated by in situ proximity ligation assay and information from on-line databases to reconstruct a cell-type specific signal transduction network. The CellNetAnalyzer were used to analyze the reconstructed network. The computational results from the minimal intervention set (MIS) showed that at least five proteins (AKT, DVL1, EGFR, IGF1R, and PDGFR) inhibited simultaneously in the reconstructed network were required for achieving the goals of drug interventions. By searching the IPA database, the proteins in the MIS, except DVL1, are single targets inhibited by clinic trial drugs to suppress cancer cells. The results suggest that a combination drug treatment may be more efficacious than a single-drug approach. Experiments should be carried out to validate the computational results in future research.