Structural and Logical Analysis of a Comprehensive Hedgehog Signaling Pathway to Identify Alternative Drug Targets for Glioma, Colon and Pancreatic Cancer

• Published in: PloS one Vol. 8; no. 7; p. e69132
• Main Authors: Chowdhury, Saikat, Pradhan, Rachana N., Sarkar, Ram Rup
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.07.2013; Public Library of Science (PLoS)
• Subjects: Aberration; Analysis; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biology; Boolean algebra; Brain tumors; Cancer; Cancer therapies; Cellular proteins; Chemical engineering; Colon; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Computation; Computer applications; Computer Simulation; Drug therapy; External stimuli; Gene expression; Genomics; Glioma; Glioma - drug therapy; Glioma - metabolism; Gliomas; Health aspects; Hedgehog protein; Hedgehog Proteins - metabolism; Humans; Laboratories; Ligands; Medical research; Medicine; Molecular interactions; Molecular Targeted Therapy; Mutation; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Parameter identification; Perturbation methods; Proteins; Regulations; Signal transduction; Signal Transduction - drug effects; Signaling; Stem cells; Structural analysis; Studies; Target recognition; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069132

Hedgehog is an evolutionarily conserved developmental pathway, widely implicated in controlling various cellular responses such as cellular proliferation and stem cell renewal in human and other organisms, through external stimuli. Aberrant activation of this pathway in human adult stem cell line may cause different types of cancers. Hence, targeting this pathway in cancer therapy has become indispensable, but the non availability of detailed molecular interactions, complex regulations by extra- and intra-cellular proteins and cross talks with other pathways pose a serious challenge to get a coherent understanding of this signaling pathway for making therapeutic strategy. This motivated us to perform a computational study of the pathway and to identify probable drug targets. In this work, from available databases and literature, we reconstructed a complete hedgehog pathway which reports the largest number of molecules and interactions to date. Using recently developed computational techniques, we further performed structural and logical analysis of this pathway. In structural analysis, the connectivity and centrality parameters were calculated to identify the important proteins from the network. To capture the regulations of the molecules, we developed a master Boolean model of all the interactions between the proteins and created different cancer scenarios, such as Glioma, Colon and Pancreatic. We performed perturbation analysis on these cancer conditions to identify the important and minimal combinations of proteins that can be used as drug targets. From our study we observed the under expressions of various oncoproteins in Hedgehog pathway while perturbing at a time the combinations of the proteins GLI1, GLI2 and SMO in Glioma; SMO, HFU, ULK3 and RAS in Colon cancer; SMO, HFU, ULK3, RAS and ERK12 in Pancreatic cancer. This reconstructed Hedgehog signaling pathway and the computational analysis for identifying new combinatory drug targets will be useful for future in-vitro and in-vivo analysis to control different cancers.