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

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.