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Review
. 2017 Dec;6(1):14.
doi: 10.1186/s40169-017-0144-7. Epub 2017 Apr 12.

Thermodynamics in cancers: opposing interactions between PPAR gamma and the canonical WNT/beta-catenin pathway

Affiliations
Review

Thermodynamics in cancers: opposing interactions between PPAR gamma and the canonical WNT/beta-catenin pathway

Yves Lecarpentier et al. Clin Transl Med. 2017 Dec.

Abstract

Cancer cells are the site of numerous metabolic and thermodynamic abnormalities. We focus this review on the interactions between the canonical WNT/beta-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR gamma) in cancers and their implications from an energetic and metabolic point of view. In numerous tissues, PPAR gamma activation induces inhibition of beta-catenin pathway, while the activation of the canonical WNT/beta-catenin pathway inactivates PPAR gamma. In most cancers but not all, PPAR gamma is downregulated while the WNT/beta-catenin pathway is upregulated. In cancer cells, upregulation of the WNT/beta-catenin signaling induces dramatic changes in key metabolic enzymes that modify their thermodynamic behavior. This leads to activation of pyruvate dehydrogenase kinase1 (PDK-1) and monocarboxylate lactate transporter. Consequently, phosphorylation of PDK-1 inhibits the pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-coenzyme A (acetyl-CoA) in mitochondria and only a part of acetyl-CoA can enter the tricarboxylic acid cycle. This leads to aerobic glycolysis in spite of the availability of oxygen. This phenomenon is referred to as the Warburg effect. Cytoplasmic pyruvate is converted into lactate. The WNT/beta-catenin pathway induces the transcription of genes involved in cell proliferation, i.e., MYC and CYCLIN D1. This ultimately promotes the nucleotide, protein and lipid synthesis necessary for cell growth and multiplication. In cancer, activation of the PI3K-AKT pathway induces an increase of the aerobic glycolysis. Moreover, prostaglandin E2 by activating the canonical WNT pathway plays also a role in cancer. In addition in many cancer cells, PPAR gamma is downregulated. Moreover, PPAR gamma contributes to regulate some key circadian genes. In cancers, abnormalities in the regulation of circadian rhythms (CRs) are observed. CRs are dissipative structures which play a key-role in far-from-equilibrium thermodynamics. In cancers, metabolism, thermodynamics and CRs are intimately interrelated.

Keywords: Aerobic glycolysis; Cancer; Circadian rhythms; Dissipative structures; PI3 K-AKT pathway; PPAR gamma; Pyruvate dehydrogenase complex; Pyruvate dehydrogenase kinase; WNT/beta-catenin; Warburg effect.

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Figures

Fig. 1
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
Fig. 2
Fig. 2
Synthetic diagram of opposing effects of PPAR gamma and canonical WNT/beta-catenin signaling in cancer. Green arrow activation; red arrow inhibition; A-CoA acetyl-CoA, GSK-3beta glycogen synthase kinase-3beta, IC lactate intracellular lactate, EC lactate extracellular lactate, GSK-3beta glycogen synthase kinase-3beta, LDH-A lactico-dehydrogenase-A, MCT-1 monocarboxylate lactate transporter-1, PI3 K-AKT phosphatidylinositol 3-kinase-protein kinase B, PDH pyruvate dehydrogenase, PDK pyruvate dehydrogenase kinase, TCF/LEF T-cell factor/lymphoid enhancer factor, PPAR gamma peroxisome proliferator-activated receptor gamma

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