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

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.