Fig. 1

Schema of interactions between the canonical WNT/beta-catenin pathway and PPAR gamma under aerobic glycolysis conditions in cancer. In the absence of the WNT ligands (“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. In the presence of the WNT ligands (“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 which prevents its degradation in the proteasome. Thus, beta-catenin accumulates in the cytosol and then translocates to the nucleus to bind TCF-LEF co-transcription factors. This induces the WNT-response gene transcription (PDK, MCT-1, MYC, CYCLIN D1). Glucose itself activates the WNT pathway. PPAR gamma inhibits the beta-catenin/TCF-LEF-induced activation of WNT target genes. PDK inhibits the PDH complex in mitochondria. Thus pyruvate cannot be fully converted into acetyl-CoA and enter the TCA cycle. MYC activates LDH-A which converts cytosolic pyruvate into lactate. MCT-1 favors lactate extrusion out of the cytosol which favors angiogenesis. MYC increases glutamine entry in the cytosol and mitochondria. MYC-induced glutamine enhances aspartate and nucleotide synthesis. APC adenomatous polyposis coli, alpha-KG alpha ceto-glutarate, DSH Dishevelled, FZD Frizzled, GSK-3beta glycogen synthase kinase-3beta, LDH lactate dehydrogenase, LRP5/6 low-density lipoprotein receptor-related protein 5/6, MCT-1 monocarboxylate lactate transporter-1, OAA: oxalo-acetic acid, PPAR gamm peroxisome proliferator-activated receptor gamma, PDH pyruvate dehydrogenase complex, PDK pyruvate dehydrogenase kinase, RTK receptor tyrosine kinase, TCF/LEF T-cell factor/lymphoid enhancer factor, TCA tricarboxylic acid, *WNT targets: PDK, MCT-1, MYC, CYCLIN D1