Metabolite sensing and signaling in cancer

Abstract

Metabolites are not only substrates in metabolic reactions, but also signaling molecules controlling a wide range of cellular processes. Discovery of the oncometabolite 2-hydroxyglutarate provides an important link between metabolic dysfunction and cancer, unveiling the signaling function of metabolites in regulating epigenetic and epitranscriptomic modifications, genome integrity, and signal transduction. It is now known that cancer cells remodel their metabolic network to support biogenesis, caused by or resulting in the dysregulation of various metabolites. Cancer cells can sense alterations in metabolic intermediates to better coordinate multiple biological processes and enhance cell metabolism. Recent studies have demonstrated that metabolite signaling is involved in the regulation of malignant transformation, cell proliferation, epithelial-to-mesenchymal transition, differentiation blockade, and cancer stemness. Additionally, intercellular metabolite signaling modulates inflammatory response and immunosurveillance in the tumor microenvironment. Here, we review recent advances in cancer-associated metabolite signaling. An in depth understanding of metabolite signaling will provide new opportunities for the development of therapeutic interventions that target cancer.

Keywords: 2HG; cancer; cancer biology; cancer stem cells; immunosurveillance; metabolic disease; metabolic intermediate; metabolic regulation; metabolite; metabolite sensing; metabolomics; oncogenic signaling; oncometabolite; sensing; signal transduction; signaling; tumor metabolism; tumor microenvironment.

Figure 1.

Oncometabolite 2-hydroxyglutarate-mediated signaling 2HG, produced by mutant isocitrate dehydrogenase 1/2 in cancer, modulates various cellular processes, including metabolic processes, epigenetic and epitranscriptomic modifications, signal transduction, and genome integrity maintenance. Tyrosine kinase FLT3 and JAK2, together with transcriptional factor Myc, regulates the 2HG-producing activity of mutant IDH. Malate dehydrogenase (MDH), lactate dehydrogenase (LDH), and phosphoglycerate dehydrogenase (PHGDH) are minor contributors of the 2HG pool. ATPS, ATP synthase; BCAT, branched-chain amino acids aminotransferase; TET, ten-eleven translocation methylcytosine dioxygenase; KDM, lysine-specific demethylase; FTO, fat mass and obesity-associated protein; KDM4A, lysine-specific demethylase 4A; ERK, extracellular signal–regulated kinase; STAT1, signal transducer and activator of transcription 1; EGLN, EGL-nine homolog enzyme; ALKBH, ALKB homolog enzymes.

Figure 2.

Metabolites modulate oncogenic signaling in cancer cells Metabolites from carbon metabolism, lipid metabolism, and amino acids metabolism modulate oncogenic signal transduction. Left, lactate binds to and stabilizes NDRG3 to enhance Raf-ERK1/2 signaling. α-HB increases the activity of DOT1L and enhances Wnt signaling by up-regulating histone methylation. Fumarate inhibits TET to increase genomic DNA methylation and promotes EMT. UDP-glucose suppresses Hu antigen R to inhibit EMT. Middle, SLCFA bind to FABP5 and suppresses PPAR β/δ signaling. MAS interact with LXR to inhibit EGFR-KRAS signaling. UFA suppress the transcriptional activity of NF-κB through an unknown mechanism. Right, 5-HIAA, a product in tryptophan catabolism, inhibits RAS/MAPK signaling. NDRG3, NDRG family member 3; α-HB, α-hydroxybutyrate; DOT1L, DOT1-like histone H3 methyltransferase; EMT, epithelial-mesenchymal transition; HuR, Hu antigen R; SLCFA, saturated long-chain fatty acids; FABP5, fatty acid-binding protein 5; MAS, meiosis-activating sterols; LXR, liver X receptor; UFA, unsaturated fatty acids; 5-HIAA, 5-hydroxyindoleacetic acid.

Figure 3.

Metabolite signaling in the tumor microenvironment Metabolite signaling in cancer-associated cells within the microenvironment. Lactate directly binds to MAVS to suppress RLR signaling and weakens cancer immunosurveillance. Kynurenine metabolism is activated in tumor-associating immune cells. Kynurenine binds to either transcription factor AHR or the cell-surface receptor GPR35 to mediate inflammatory signaling. In Th1 cells, glutamine-derived α-KG increases the expression of Tbet, through an unknown mechanism, and promotes Th1 cell differentiation. Bile acid triggers the release of CXCL16, which further acts on endothelial cells and NK cells to enhance antitumor immunosurveillance. AHR, aryl hydrocarbon receptor; GPR35, G protein–coupled receptor 35; Tbet, T-box transcription factor.