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.

High-Dose Dexamethasone Manipulates the Tumor Microenvironment and Internal Metabolic Pathways in Anti-Tumor Progression

“…Moreover, important proteins involved in aerobic glycolysis such as Glut1, Hk2, Pgk1, and Idh3a were decreased in tumors. Previous studies demonstrated that activation of Pparg could impair the aerobic glycoysis process via inhibiting Pgk1 and Glut1 function [18,43]. These findings indicated that high-dose DEX-inhibited tumor growth via the reduction of glucose metabolism enzymes expression, which starves the cancer cells of ATP and important amino acids/nucleic acid precursors.…”

RETRACTED ARTICLE: Coffee component hydroxyl hydroquinone (HHQ) as a putative ligand for PPAR gamma and implications in breast cancer

“…PPARγ receptor is a member of the nuclear receptor superfamily which upon ligand activation undergoes heterodimerization with retinoic acid-like receptor (RXR) and is translocated to the nucleus where it recognizes a specific sequence - the peroxisome proliferator response element (PPRE) located within promoters of target genes, and acts as a transcription regulator for genes involved in proliferation, cell differentiation, apoptosis, angiogenesis, inflammation, organogenesis, and lipid and carbohydrate metabolism and energy homeostasis [3-5]. Two isoforms of PPARγ have been identified (PPARγ 1 and PPARγ 2), with a wide tissue distribution among various animal species [6].…”

Proteomic characterization of peroxisome proliferator‐activated receptor‐γ (PPARγ) overexpressing or silenced colorectal cancer cells unveils a novel protein network associated with an aggressive phenotype

“…Another group of differentially expressed proteins, accounting for 27% in HT29 and 20% in HCT116 cell models, were metabolism‐related proteins and the majority of them were upregulated in HCT116 PPARγ, confirming the well‐established role of PPARγ as a regulator of lipid metabolism and glucose homoeostasis (Robbins and Nie, 2011; Janani and Ranjitha Kumari, 2014). Accordingly, PGK1, a critical enzyme of the glycolytic pathway that has recently been proven as a novel target of PPARγ (Shashni et al., 2012), was downregulated in HT29 sh‐PPARγ and validated by western blotting. Also proteins implicated in cellular/protein fate control were among those differentially expressed both in HT29 sh‐PPARγ (27%) and HCT116 PPARγ (23%), including several heat shock proteins (HSPs).…”