The Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions

Abstract

The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth.

Keywords: HIF-1α; VEGF; WNT/β-catenin pathway; Warburg effect; aerobic glycolysis; angiogenesis; autophagy; cancer; glutaminolysis; lactate; metabolic reprogramming; normoxia.

Figure 1

The activated and inactivated WNT/β-catenin pathway.

Figure 2

The WNT/β-catenin pathway and the Warburg effect. WNT ligands bind with the Frizzled/LRP 5/6 receptor complex, leading to LRP phosphorylation of the AXIN/APC/GSK-3β complex. β-catenin accumulates in the cytoplasm to translocate to the nucleus. The WNT-process transcription activity is then stimulated. MCT-1 enhances lactate release out of the cell. The stimulation of the PI3K/Akt pathway is associated with the activation of the glucose process. Increased levels of aerobic glycolysis are associated with higher lactate production and a decrease in mitochondrial respiration. HIF-1α activation leads to the cytoplasmic pyruvate being shunted into lactate by MDH-A induction. The pyruvate cannot then be fully converted into acetyl-CoA and enter the TCA cycle. The entry of glucose into the TCA cycle is modulated by the pyruvate dehydrogenase complex (PDH). A decrease in PDH inhibits the activity of the mitochondria in several cancers [115]. In tumor cells, the activation of the WNT/β-catenin pathway enhances aerobic glycolysis [116]. PDK-1 is activated in vitro and in living colon tumor cells [117] and there is a decrease in the conversion of pyruvate into acetyl-CoA in mitochondria [118]. PDK-1, LDH-A and MCT-1 are stimulated in cancer cells [57,119]. c-Myc and cyclin D1 also stimulate aerobic glycolysis [120]. The activation of c-Myc and PI3K/Akt signaling leads to the stimulation of HIF-1α activity, which inhibits glucose entry into the TCA cycle [121,122]. The stimulation of HIF-1α increases the expression of Glut, HK, PK, PDK-1 and LDH-A [20,123,124]. Glut allows the entry of glucose into the cytoplasm where glycolysis ensues. HK phosphorylates glucose during the first stage of glycolysis. PK controls the production of pyruvate during the last stage of glycolysis. PDH stimulates the entry of pyruvate into the oxidative phosphorylation process and thus the tricarboxylic acid (TCA) cycle within the mitochondria. Activation of HIF-1α stimulates PDK-1, inactivating PDH. The stimulation of LDH-A leads to the conversion of pyruvate into lactate. Abbreviations: GSK: glycogen synthase kinase, DSH: disheveled, APC: adenomatous polyposis coli, HIF: hypoxic inducible factor, RTK: tyrosine kinase receptor, Glut: glucose transporter, HK: hexokinase, PKM2: pyruvate kinase M2, LDH: lactate dehydrogenase, PDK: pyruvate dehydrogenase kinase, TCA: tricarboxylic cycle.

Figure 3

The WNT/β-catenin pathway and its different actions in cancer processes. The WNT plays a major role in cancer processes by interacting with the STAT3 pathway, leading to tumor growth, by stimulating cyclin D1 and c-Myc, responsible for cell proliferation and then for the glutaminolysis mechanism responsible for the nucleotide synthesis. β-catenin directly activates RTK, which in turn stimulates the PI3K/Akt pathway leading to the inactivation of the GSK-3β, a major inhibitor of β-catenin. Activated Akt stimulates MMP-2 and MMP-9, which are responsible for the invasiveness. The double action of β-catenin and the PI3K/Akt pathway for the activation of the HIF-1α enhances the stimulation of the PDK, which in turn inactivates the PDH and stops the TCA cycle. The TCA cycle arrest leads to lipid synthesis and protein accumulation in cancers. Moreover, LDH-1 is directly responsible for the production of lactate and its translocation over the cell by MCT-1, which in turn stimulates angiogenesis. Abbreviations: GSK: glycogen synthase kinase, HIF: hypoxic inducible factor, RTK: tyrosine kinase receptor, LDH: lactate dehydrogenase, PDK: pyruvate dehydrogenase kinase, TCA: tricarboxylic cycle, MCT: monocarboxylate transporter.

Figure 4

Interplay between the WNT/β-catenin pathway, aerobic glycolysis and autophagy. The interactions between WNT, PI3K/Akt pathway, mTORC1, HIF and JNK result in stimulating both glycolysis and autophagy, involving several glycolytic enzymes (including, glucose, G6P, F6P, FDP, PEP, pyruvate producing lactate over the cell by MCT). Abbreviations: G-6-P: glucose 6 phosphate, F-6-P: fructose 6 phosphate, FDP: fructose diphosphate, PFK: phosphofructokinase, PEP: phosphoenolpyruvate, JNK: Jun N-terminal kinase, HIF: hypoxic inducible factor, mTORC1: mechanistic target of rapamycin C1.

Figure 5

Interplay between the WNT/β-catenin pathway, aerobic glycolysis and glutaminolysis. c-Myc has been observed to play a role in the activation of genes involved in glutamine metabolism, including the glutamine transporter ASCT2 (or SLC1A1) and glutaminase [271]. Moreover, β-catenin can control glutamine metabolism and glutaminolysis by directly acting on c-Myc [272]. Aerobic glycolysis, directly modulated by the WNT/β-catenin pathway stimulates the different receptors of the glycose pathway and activates the MCT (monocarboxylate transporters) to translocate the lactate over the cell. The process of glutaminolysis, indirectly activated by the aerobic glycolysis and β-catenin signaling leads to the down-production of ROS, which in turn activates the β-catenin. Abbreviations: MCT: monocarboxylate transporter, Glut-1: glucose transporter 1, ASCT2: glutamine transporter 2, ROS: reactive oxygen species.

Figure 6

Interaction between the WNT/β-catenin pathway and the Hippo pathway. Crosstalk between the YAP/TAZ and TGF-β pathways is observed. TAZ interacts with Smad2/Smad3 [285] to induce the nuclear transfer of Smad2/3 and then to transcribe the PAI-1 and Smad target genes. In the cytosol, TAZ is bound to the WNT/β-catenin signaling by a TAZ/β-catenin complex [279]. WNT stimulation is associated with the inhibition of the β-catenin destruction complex, resulting in cytosolic β-catenin accumulation and its nuclear translocation for stimulating the different WNT targets. Following WNT activation, TAZ decreases the DSH phosphorylation and liberates it from the destruction complex. The destruction complex is destroyed because YAP and TAZ dissociate from the complex. Following TGF-β1 stimulation, AXIN leads to the enhancement of the tail-phosphorylation of Smad2/3. The stimulated Smad2/3-Smad4 complex interacts with TAZ and YAP and translocates to the nucleus for the stimulation of the Smad targets. TGF-β1 leads to Smad2/3 and PI3K/Akt signaling overactivation. The nuclear translocation of β-catenin blocks the degradation of TAZ. This relationship of TAZ with the WNT/β-catenin pathway is independent of its role as a mediator of the Hippo pathway. When WNT/β-catenin signaling activity is decreased, the cytoplasmic YAP/TAZ specifically interacts with AXIN [280].