Thermodynamics in Gliomas: Interactions between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma

Abstract

Gliomas cells are the site of numerous metabolic and thermodynamics abnormalities with an increasing entropy rate which is characteristic of irreversible processes driven by changes in Gibbs energy, heat production, intracellular acidity, membrane potential gradient, and ionic conductance. We focus our review on the opposing interactions observed in glioma between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In gliomas, WNT/beta-catenin pathway is upregulated while PPAR gamma is downregulated. Upregulation of WNT/beta-catenin signaling induces changes in key metabolic enzyme that modify their thermodynamics behavior. This leads to activation pyruvate dehydrogenase kinase 1(PDK-1) and monocarboxylate lactate transporter 1 (MCT-1). Consequently, phosphorylation of PDK-1 inhibits pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and in TCA (tricarboxylic acid) cycle. This leads to aerobic glycolysis despite the availability of oxygen, named Warburg effect. Cytoplasmic pyruvate is, in major part, converted into lactate. The WNT/beta-catenin pathway induces also the transcription of genes involved in cell proliferation, cell invasiveness, nucleotide synthesis, tumor growth, and angiogenesis, such as c-Myc, cyclin D1, PDK. In addition, in gliomas cells, PPAR gamma is downregulated, leading to a decrease in insulin sensitivity and an increase in neuroinflammation. Moreover, PPAR gamma contributes to regulate some key circadian genes. Abnormalities in the regulation of circadian rhythms and dysregulation in circadian clock genes are observed in gliomas. Circadian rhythms are dissipative structures, which play a key role in far-from-equilibrium thermodynamics through their interactions with WNT/beta-catenin pathway and PPAR gamma. In gliomas, metabolism, thermodynamics, and circadian rhythms are tightly interrelated.

Keywords: PI3K-Akt pathway; PPAR gamma; WNT/beta-catenin pathway; Warburg effect; aerobic glycolysis; circadian rhythms; gliomas; lactate.

Figure 1

Role of WNT/beta-catenin pathway on aerobic glycolysis in gliomas. In the presence of WNT ligands (“on state”), WNT binds both Frizzled and LRP 5/6 receptors to initiate LRP phosphorylation of the Axin/APC/GSK-3beta complex. Beta-catenin phosphorylation is inhibited which prevents its degradation in the proteasome. 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, c-Myc, cyclin D, MCT-1). Glucose itself activates the WNT pathway. MCT-1 favors lactate extrusion out of the cytosol which favors angiogenesis. WNT/beta-catenin pathway stimulates tyrosine kinase receptors (TKRs) activation. Activation of PI3K/Akt increases glucose metabolism. Akt-transformed cells protect against reactive oxygen species stress (ROS stress) by inducing HIF-1alpha, which suppresses glucose entry into the TCA cycle. HIF-1alpha induced PDK1 phosphorylates PDH, which resulting in cytosolic pyruvate being shunted into lactate through induction of LDH-A. PDK inhibits the PDH complex in mitochondria, thus pyruvate cannot be fully converted into acetyl-CoA and enter the TCA cycle. c-Myc and cyclin D also activates LDH-A which converts cytosolic pyruvate into lactate. c-Myc increases glutamine entry in the cytosol and mitochondria. c-Myc-induced glutamine enhances aspartate and nucleotide synthesis.

Figure 2

Opposing effects of PPAR gamma and canonical WNT/beta-catenin signaling in gliomas. Circadian rhythms disorders are observed in Gliomas, with decreasing of Per and increasing of Bmal1 and Clock. Overexpression of Bmal1 induces activation of WNT pathway. Upregulation of canonical WNT and downregulation of PPAR gamma are observed in gliomas. PI3K/Akt pathway and PGE2 also activate beta-catenin. The activation of beta-catenin induces transcription of WNT targets genes such as PDK, MCT-1, c-Myc, and cyclin D. PDK inhibits the PDH complex in mitochondria, thus pyruvate cannot be fully converted into acetyl-CoA and enter the TCA cycle. c-Myc and cyclin D activates LDH-A which converts cytosolic pyruvate into lactate. MCT-1 favors lactate extrusion out of the cytosol which favors angiogenesis. This effect is called aerobic glycolysis. Activation of WNT/beta-catenin pathway induces aerobic glycolysis, and then results in cell proliferation, nucleotide synthesis, protein synthesis and angiogenesis in gliomas. PPAR gamma agonists induce activation of Bmal1 and the formation of heterodimers Clock/Bmal1, and then inhibit the WNT pathway. PPAR gamma agonists directly inhibit activation of beta-catenin and its nuclear translocation and then inhibit transcription of WNT targets genes. Using PPAR gamma agonists may interest to stop gliomas progression through inhibition of aerobic glycolysis via inactivation of canonical WNT/beta-catenin pathway.