The Pentose Phosphate Pathway: From Mechanisms to Implications for Gastrointestinal Cancers

Abstract

The pentose phosphate pathway (PPP), traditionally recognized for its role in generating nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate (R5P), has emerged as a critical metabolic hub with involvements in various gastrointestinal (GI) cancers. The PPP plays crucial roles in the initiation, development, and tumor microenvironment (TME) of GI cancers by modulating redox homeostasis and providing precursors for nucleotide biosynthesis. Targeting PPP enzymes and their regulatory axis has been a potential strategy in anti-GI cancer therapies. In this review, we summarize the regulatory mechanisms of PPP enzymes, elucidate the relationships between the PPP and TME's elements, and discuss the therapeutic potential of targeting the PPP in GI cancers.

Keywords: gastrointestinal cancers; nucleotide biosynthesis; pentose phosphate pathway; redox homeostasis; tumor microenvironment.

Figure 1

Schematic drawing of the metabolic flux of glycolysis, oxPPP, and non-oxPPP. Abbreviations: 2PG: 2-Phosphoglycerate; 3PG: 3-phosphoglycerate; 6PDGL: 6-phosphogluconolactone; 6PG: 6-phosphogluconate; DHAP: dihydroxyacetone phosphate; E4P: erythrose 4-phosphate; F1,6BP: Fructose-1,6-bisphosphate; F6P: fructose-6-phosphate; G6P: glucose-6-phosphate; GADP: glyceraldehyde 3-phosphate; GLUT: glucose transporter; HK: hexokinase; LDH: lactate dehydrogenase; NAD: nicotinamide adenine dinucleotide; NADPH: nicotinamide adenine dinucleotide phosphate; PEP: phosphoenolpyruvate; PGAM: phosphoglycerate mutase; PFK1: phosphofructokinase-1; R5P: ribose 5-phosphate; Ru5P: ribulose 5-phosphate; S7P: sedoheptulose 7-phosphate; TAL: transaldolase; TKT: transketolase; TPI: triosephosphate isomerase; and Xu5P: xylulose 5-phosphate.

Figure 2

Overview of the regulatory network involving G6PD in GI cancers. Abbreviations: Aldob: aldolase B; BAG3: Bcl-2 associated athanogene 3; CRC: colorectal cancer; ESCC: esophageal squamous cell carcinoma; G6PD: glucose-6-phosphate dehydrogenase; GC: gastric cancer; GSK-3β: glycogen synthase kinase-3β; GLUT1: glucose transporter 1; HBx: hepatitis B virus X protein; HCC: hepatocellular carcinoma; HnRNPK: heterogeneous nuclear ribonuclear protein K; KEAP1: kelch-like ECH-associated protein 1; ID1: inhibitor of differentiation 1; IL-6: interleukin-6; MDM2: murine double minute 2; NeuroD1: neuronal differentiation 1; Nrf2: nuclear factor erythroid 2-related factor 2; OGT: O-GlcNAc transferase; PAK4: p21-activated kinase 4; PBX3: Pre-B-cell leukemia transcription factor 3; PDAC: pancreatic ductal adenocarcinoma; PLK1: polo-like kinase 1; Pol ι: DNA polymerase iota; PSC: pancreatic stellate cell; PTEN: phosphatase and tensin homolog located on chromosome 10; Rac1: ras-related C3 botulinum toxin substrate 1; RF: regulatory factor; SDF-1α: stromal-derived factor-1 alpha; SOX9: sex-determining region Y-box 9; Tcl1: T cell leukemia 1; TF: transcription factor; TP53: tumor protein 53; and YY1: Yin Yang 1.

Figure 3

The relationships between the PPP and TME’s elements in GI cancers. Abbreviations: AMPK: AMP-activated protein kinase; AMOTL1: angiomotin like 1; ATP: adenosine triphosphate; CAFs: cancer-associated fibroblasts; CARM1: coactivator-associated arginine methyltransferase 1; CM: conditioned medium; FAK: focal adhesion kinase; G3P: glycerol-3-phosphate; G6P: glucose-6-phosphate; G6PD: glucose-6-phosphate dehydrogenase; HIF1α: hypoxia-inducible factors 1α; IFNγ: interferon-γ; IL-6: interleukin-6; MMP1: matrix metalloproteinase-1; MUC1: mucin 1; NRF2: nuclear factor erythroid 2-related factor 2; OXPHOS: oxidative phosphorylation; PCK1: phosphoenolpyruvate carboxykinase 1; PFKFB4: phosphofructokinase-fructose bisphosphatase 4; PI3K: phosphoinositide 3-kinase; POX: proline oxidase; PPP: pentose phosphate pathway; PFK1: phosphofructokinase-1; RPIA: ribose-5-phosphate isomerase A; ROS: reactive oxygen species; SDF-1α: stromal-derived factor-1α; SGK1: serum and glucocorticoid kinase-1; S7P: sedoheptulose-7-phosphate; TME: tumor microenvironment; TNFα: tumor necrosis factor α; and YAP/TAZ: yes-associated protein and transcriptional coactivator with PDZ-binding motif.