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.
Highlights
Gliomas are the most frequent primary brain tumors
Gliomas are classified into grade I to IV based on the criteria set by World Health Organization, with a higher-grade corresponding to more aggressive tumors
From a thermodynamic viewpoint and among numerous cellular processes involved in gliomas, the opposite profile of the canonical WNT/beta-catenin pathway and PPAR gamma in gliomas play a key role in both aerobic glycolysis (Warburg effect) and disruption of circadian rhythms
Summary
Gliomas are the most frequent primary brain tumors. Around 30 percent of all brain and central nervous system tumors and 80 percent of all malignant brain tumors are gliomas. Upregulation of the WNT/beta-catenin signaling induces changes in key metabolic enzymes that modify their thermodynamics behavior. This leads to activation of pyruvate dehydrogenase kinase-1 (PDK-1) and monocarboxylate lactate transporter-1 (MCT-1) (Bienz and Clevers, 2000; Pate et al, 2014). The WNT/beta-catenin pathway induces the transcription of genes involved in cell proliferation (c-Myc, cyclin D1, PDK). From a thermodynamic viewpoint and among numerous cellular processes involved in gliomas, the opposite profile of the canonical WNT/beta-catenin pathway and PPAR gamma in gliomas play a key role in both aerobic glycolysis (Warburg effect) and disruption of circadian rhythms. WNT signaling has an important role in the control of energy intake and modulation of the energy balance (Helfer and Tups, 2016)
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