Interactions between PPAR Gamma and the Canonical Wnt/Beta-Catenin Pathway in Type 2 Diabetes and Colon Cancer

Abstract

In both colon cancer and type 2 diabetes, metabolic changes induced by upregulation of the Wnt/beta-catenin signaling and downregulation of peroxisome proliferator-activated receptor gamma (PPAR gamma) may help account for the frequent association of these two diseases. In both diseases, PPAR gamma is downregulated while the canonical Wnt/beta-catenin pathway is upregulated. In colon cancer, upregulation of the canonical Wnt system induces activation of pyruvate dehydrogenase kinase and deactivation of the pyruvate dehydrogenase complex. As a result, a large part of cytosolic pyruvate is converted into lactate through activation of lactate dehydrogenase. Lactate is extruded out of the cell by means of activation of monocarboxylate lactate transporter-1. This phenomenon is called Warburg effect. PPAR gamma agonists induce beta-catenin inhibition, while inhibition of the canonical Wnt/beta-catenin pathway activates PPAR gamma.

Figure 1

A model of interactions between the canonical Wnt/beta-catenin pathway and PPAR gamma under aerobic glycolysis conditions in colon cancer. In the absence of the Wnt ligand (“off state”), cytosolic beta-catenin is phosphorylated by GSK-3 beta. APS and AXIN combine with GSK-3 beta and beta-catenin to enhance the destruction process in the proteasome (beta-catenin proteasomal degradation: CPD). In the presence of the Wnt ligand (“on state”), Wnt binds both Frizzled and LRP5/6 receptors to initiate LRP phosphorylation and dishevelled-mediated Frizzled internalization. This leads to dissociation of the AXIN/APC/GSK-3 beta complex. Beta-catenin phosphorylation is inhibited. Thus, beta-catenin accumulates in the cytosol and then translocates to the nucleus to bind TCF-LEF cotranscription factors, which induce the Wnt-response gene transcription (PDK, MCT-1, cMyc, and cyclin D1). Glucose itself activates the Wnt pathway. PPAR gamma via APC activates CPD. PPAR gamma inhibits the beta-catenin-TCF/LEF complex. Beta-catenin binds PPAR gamma CBD. PDK inhibits the PDH complex in mitochondria. Thus pyruvate cannot be converted into acetyl-CoA and enters the TCA cycle. Myc activates LDH-A which converts cytosolic pyruvate into lactate. MCT-1 favors lactate secretion from the cytosol which favors angiogenesis. cMyc increases glutamine entry in the cytosol and mitochondria. Myc-induced glutamine enhances nucleotide synthesis. Abbreviations are as follows: adenomatous polyposis coli (APC); alpha ceto-glutarate (a-KG); beta-catenin proteasomal degradation: CPD; catenin binding domain (CBD); Dishevelled (Dsh); Frizzled (Fzd); glycogen synthase kinase-3beta (GSK-3beta); lactate dehydrogenase (LDH); low-density lipoprotein receptor-related protein 5/6 (LRP5/6); monocarboxylate lactate transporter-1 (MCT-1); peroxisome proliferator-activated receptor gamma (PPAR gamma); pyruvate dehydrogenase complex (PDH); pyruvate dehydrogenase kinase (PDK); T-cell factor/lymphoid enhancer factor (TCF/LEF); tricarboxylic acid (TCA); ∗: Wnt targets: PDK, cMyc, MCT-1, and cyclin D1.

Figure 2

A schematic representation of interactions between PPAR gamma and the canonical Wnt/beta-catenin pathway in type 2 diabetes and colon cancer. Green arrow: activation; red arrow: inhibition; abbreviations are as follows: acetyl-CoA (A-CoA); glucokinase (GK); glucose transporter (GLUT); intracellular lactate (IC lactate); extracellular lactate (EC lactate); lactate dehydrogenase-A (LDH-A); monocarboxylate lactate transporter-1 (MCT-1); pyruvate dehydrogenase (PDH); pyruvate dehydrogenase kinase (PDK); peroxisome proliferator-activated receptor gamma (PPAR gamma).