1 Introduction Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily of ligand-activated transcription factors. Upon ligand activation, PPAR translocates from cytoplasm to nucleus and heterodimerizes with retinoid X receptor (RXR) to regulate gene expression. hree isoforms (α, β, and γ) for PPAR have been identiied so far in Xenopus, mouse, human, rats, and hamsters. he PPAR subtypes share a highly conserved DNA-binding domain that matches with speciic DNA sequences known as peroxisome proliferator response elements (PPREs). hese PPAR isoforms are encoded by diferent genes, perform diferent functions and exhibit diferent tissue localizations (Issemann & Green, 1990; Dreyer et al., 1992; Kliewer et al., 1994; Rosen et al., 2000; Zhu et al., 1993; Reddy & Mannaerts, 1994). Imbalances in expression of target genes that have a pivotal role in regulating metabolic syndrome and cancer through atherogenic metabolic triad/lipid triad metabolism has recently been noted to be modulated by PPARs (Smith & Muscat, 2006). 15-Deoxy-Δ 12, 14 -prostaglandin J 2 (15d-PGJ2) is a natural ligand for PPARγ and thiazolidinediones are synthetic ligands (Houseknecht et al., 2002). It is prudent to note that the expression of PPARγ in tumor breast tissue is signiicantly higher than in normal breast epithelium. Toward this end, development of a new class of anticancer drugs through a new approach employing PPARγ activators RESEARCH ARTICLE Glycolytic enzymes PGK1 and PKM2 as novel transcriptional targets of PPARγ in breast cancer pathophysiology Babita Shashni 1 , Kishore R. Sakharkar 2 , Yukio Nagasaki 3–5 , and Meena K. Sakharkar 1 1 Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan, 2 Omics Vista, Singapore, Singapore, 3 Department of Materials Sciences, Graduate School of Pure and Applied Sciences, University of Tsukuba, Ibaraki, Japan, 4 Master’s School of Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan, and 5 Satellite Laboratory, International Center for Materials Nanoarchitectonics (WPI-MANA), National Institute for Materials Science (NIMS), University of Tsukuba, Ibaraki, Japan Abstract Peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ in breast cancer pathophysiology are unclear. In this study, we carried out 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 PPAR-associated conserved motif (PACM) motifs. We further constructed protein-protein interaction network, disease gene network and gene ontology (GO) analyses to identify novel key genes for experimental validation. We identiied two genes in the glycolytic pathway (phosphoglycerate kinase 1 (PGK1) and pyruvate kinase M2 (PKM2)) at the ATP production steps and experimentally validated their repression by PPARγ in two breast cancer cell lines MDA-MB-231 and MCF-7. Further analysis suggested that this repression leads to decrease in ATP levels and apoptosis. These investigations will help us in understanding the molecular mechanisms by which PPARγ regulates the cellular energy pathway and the use of its ligands in human breast cancer therapeutics. Keywords: PPARγ, glycolysis, PGK1, PKM2, breast cancer Address for Correspondence: Meena K. Sakharkar, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. Tel.: +81-29-853-8834. E-mail: msakharkar@gmail.com (or) meena.sak.gn@u.tsukuba.ac.jp (Received 17 August 2012; revised 30 September 2012; accepted 02 October 2012) Journal of Drug Targeting, 2012; Early Online: 1–14 © 2012 Informa UK, Ltd. ISSN 1061-186X print/ISSN 1029-2330 online DOI: 10.3109/1061186X.2012.736998 Journal of Drug Targeting Downloaded from informahealthcare.com by Tsukuba University Library on 11/06/12 For personal use only.