title: Glycolytic enzymes PGK1 and PKM2 as novel transcriptional targets of PPARγ in breast cancer pathophysiology.
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 identified 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.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Babita
authors.initials: B
authors.lastname: Shashni
authors.forename: Kishore R
authors.initials: KR
authors.lastname: Sakharkar
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nagasaki
authors.forename: Meena K
authors.initials: MK
authors.lastname: Sakharkar
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D030541:Databases, Genetic; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D010735:Phosphoglycerate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D054730:Protein Interaction Domains and Motifs; D020218:Response Elements / Q000235:genetics; D013963:Thyroid Hormones / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000255:Adenosine Triphosphate; D002352:Carrier Proteins; D008024:Ligands; D008565:Membrane Proteins; D047495:PPAR gamma; D010735:Phosphoglycerate Kinase; D015230:Prostaglandin D2; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C477819:15-deoxyprostaglandin J2; C577282:PGK1 protein, human