Vallée Alexandre, Lecarpentier Yves, Guillevin Rémy, Vallée Jean-Noël
Experimental and Clinical Neurosciences Laboratory, Institut National de la Santé et de la Recherche Médicale U1084, University of PoitiersPoitiers, France.
Laboratoire de Mathématiques et Applications, UMR Centre National de la Recherche Scientifique 7348, Université de PoitiersPoitiers, France.
Front Physiol. 2017 May 30;8:352. doi: 10.3389/fphys.2017.00352. eCollection 2017.
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.
胶质瘤细胞存在众多代谢和热力学异常，其熵率不断增加，这是由吉布斯自由能变化、产热、细胞内酸度、膜电位梯度和离子电导率驱动的不可逆过程的特征。我们的综述重点关注胶质瘤中经典WNT/β-连环蛋白通路与PPARγ之间的相反相互作用及其代谢和热力学意义。在胶质瘤中，WNT/β-连环蛋白通路上调而PPARγ下调。WNT/β-连环蛋白信号通路的上调会诱导关键代谢酶的变化，从而改变其热力学行为。这导致丙酮酸脱氢酶激酶1（PDK-1）和单羧酸乳酸转运蛋白1（MCT-1）的激活。因此，PDK-1的磷酸化会抑制丙酮酸脱氢酶复合体（PDH）。这样一来，大部分丙酮酸无法在线粒体和三羧酸（TCA）循环中转化为乙酰辅酶A。尽管有氧气供应，这仍导致有氧糖酵解，即瓦伯格效应。细胞质中的丙酮酸大部分转化为乳酸。WNT/β-连环蛋白通路还会诱导参与细胞增殖、细胞侵袭、核苷酸合成、肿瘤生长和血管生成的基因转录，如c-Myc、细胞周期蛋白D1、PDK。此外，在胶质瘤细胞中，PPARγ下调，导致胰岛素敏感性降低和神经炎症增加。而且，PPARγ有助于调节一些关键的昼夜节律基因。在胶质瘤中观察到昼夜节律调节异常和昼夜节律时钟基因失调。昼夜节律是耗散结构，通过与WNT/β-连环蛋白通路和PPARγ的相互作用，在远离平衡的热力学中发挥关键作用。在胶质瘤中，代谢、热力学和昼夜节律紧密相关。
