Integrative Approaches for Drug Discovery – PPAR Gamma as a Case Study

The pharmaceutical industry is spending increasingly large amounts of money on the discovery and development of novel medicines, but this investment is not adequately paying off in an increased rate of newly approved drugs by the FDA. Accumulated knowledge on genomic information, systems biology, and disease mechanisms provide an unprecedented opportunity to elucidate the genetic basis of diseases, and to discover novel therapeutic targets from genomic data. With hundreds to a few thousand potential targets available in the human genome alone, and the rise in the role of multi-drug therapies for complex diseases, there is an urgent need to understand the relationships between diseases and genes, and drugs and targets. These data can further be used for mapping cellular pathways and gene networks underlying the onset of disease and the possible mechanisms of pharmacological treatments that ameliorate the specific disease phenotype and help understand the relationships between diseases, genes, drugs, targets, and phenotypes. One key multi-disease target is PPAR Peroxisome proliferator-activated receptor

γ

(PPAR

γ

). PPAR-gamma is a nuclear receptor and plays important roles in breast cancer cell proliferation. The complexity of the underlying biochemical and molecular mechanisms of breast cancer and the involvement of PPAR

γ

in breast cancer pathophysiology is unclear. We have carried out computational prediction of the Peroxisome Proliferator Response Element (PPRE) motifs in 2332 genes reported to be involved in breast cancer in literature. A total of 178 genes were found to have PPRE (DR1/DR2) and / or PACM (PPAR-associated conserved motif) motifs. We further analysed the protein-protein interaction networks, disease gene networks and gene ontology to identify novel key genes for experimental validation. Four transcriptional targets of PPAR-gamma - MnSOD (ROS balance), NHE1 (pH maintenance), PGK1 (Glycolysis) and PKM2 (Glycolysis/metabolic regulator) were validated in vitro and PPAR-gamma ligands were found to repress these genes in two breast cancer cell lines MDA-MB-231 and MCF-7 and cause apoptosis. These findings have implications in breast cancer therapeutics and will also help in understanding the molecular mechanisms by which PPAR

γ

regulates the cellular energy pathway.