Table 1.
Genetic control and dysfunctions in cancer metabolic reprogramming.
| Metabolism | Oncogenic Protein | Metabolic Enzyme Targets | Mechanisms and Phenotype |
|---|---|---|---|
| Glycolysis, glutaminolysis, and amino acid synthesis | Myc | GLUT, HK2, and PFK [40,41]; LDH and MCT1 [42,43]; SLC1A5 and SLC38A5 [44]; GLS [45]; GLUD and transaminase [46,47]; G6PD and TKT [48] |
Gain-of-function mutation enhances cell cycle progression and metabolism in cancer by upregulating the expression of glucose transporters and the majority of glycolytic enzymes, promoting glycolysis and glutaminolysis. |
| Glycolysis, tricarboxylic acid cycle, and fatty acid oxidation | p53 | GLUT1/4 [49]; TIGAR [50]; LDH and PDH [51]; CPT1 and LPIN1 [52,53] | A loss of p53 alters the metabolism in cancer cells by downregulating several enzymes and transporters inhibiting mitochondrial respiration, glycolysis, and apoptosis. |
| Fatty acid synthesis and glycolysis | PTEN | PI3K/AKT [8] | Mutations or a loss of PTEN result in negative regulation of the PI3K/AKT signaling pathway and in turn intracellular metabolic reprogramming, promoting the growth and proliferation of cancer cells. |
| Glycolysis, glutaminolysis, and amino acid synthesis | Ras | PI3K/AKT/mTOR [8]; RAF/MEK/ERK [8]; Myc [8]; |
Oncogenic mutations lead to the upregulation of enzymes, resulting in tumor metabolic reprogramming and promotion of cell proliferation and survival. |
| Glycolysis and fatty acid synthesis | PIK3CA | PI3K/AKT [8] | Mutations lead to the activation of the PI3K/AKT pathway and enhance intracellular signal transduction, which leads to subsequent metabolic reprogramming of cancer cells. |
| Glycolysis and glutaminolysis | EGFR | PI3K/AKT; RAF/MEK/ERK [54] |
EGFR signaling pathways activate lipogenesis through PI3K/AKT and MAPK pathways, leading to increased de novo lipid synthesis and alterations in lipid metabolism that support cancer cell growth and proliferation. |
| Glycolysis | PDK1 | PDHC [55] | Activation promotes a shift from oxidative phosphorylation to glycolysis by inhibiting the pyruvate dehydrogenase complex, thereby redirecting cellular metabolism to support tumorigenesis and metastasis. |
| Glycolysis, de novo lipogenesis, and protein synthesis | NF1 | Neurofibromin [56] | Loss-of-function mutations alter neurofibromin expression, increase RAS and PI3K/AKT pathway signaling, constraining oxidative ATP production, restrict energetic flexibility, and increase glutamine influx into TCA intermediates, expanding lipid pools (especially triglycerides) and altering the synergy between metabolic inhibitors and traditional targeted inhibitors. |
| Glycolysis, tricarboxylic acid cycle, and fatty acid synthesis | HIF-1α | HK2, PDK1, LDHA [57,58] | In response to hypoxia, HIF-1α upregulates the activation of genes involved in glycolysis and metabolism, cell proliferation, angiogenesis, invasion, and metastasis. |
| Glycolysis, protein synthesis, and lipid metabolism | TSC2 | Rheb [59] | Loss-of-function mutations lead to abnormal activation of the mTOR pathway through increased Rheb activity. This results in altered protein synthesis, lipid metabolism, and glucose metabolism. |
| Glycolysis and fatty acid oxidation | SIRT1 | β-catenin [60] | When upregulated in response to glucose deficiency and oxidative stress, SIRT1 deacetylates β-catenin, causing its translocation from the nucleus to the cytoplasm, attenuates glycolysis, and positively correlates with fatty acid oxidation. This promotes the shift in glycolipid metabolism, facilitating tumor development in colorectal carcinoma. |
| Glycolysis, amino acid metabolism, lipid metabolism, and bile acid metabolism | YAP/TAZ | GLUT3 [61]; HK2 [62]; PFKFB3 [63]; SLC1A5 and SLC7A5 [64,65]; GOT1 and PSAT1 [66,67] | Overactivation promotes glycolysis by increasing GLUT3, HK2, and PFKFB3 expression, enhancing glutamine metabolism by upregulating transporters and enzymes. It modulates lipid and bile acid accumulation, aiding cancer metastasis. |
| Glycolysis and fatty acid oxidation | LKB1 | AMPK 1/2, MARK 1/2/3/4, SIK 1/2/3, NUAK 1/2, and SNRK [68] | LKB1 deficiency leads to the dysregulation of cellular energy homeostasis and contributes to the metabolic reprogramming of cancer cells, which induces excess glycolysis, the primary energy supply for cancer cells, enhancing their cellular growth and proliferation. |
| Glycolysis and tricarboxylic acid cycle | FH | PDHA1 [69] | Mutations lead to metabolic reprogramming characterized by increased glycolytic flux, a shift to glutamine as the primary carbon source, the induction of pseudohypoxia, alterations in lipid biosynthesis, and enhanced arginine metabolism, collectively promoting a favorable environment for cancer progression. |
| Glycolysis | PGAM1 | Wnt/β-catenin [70]; BCL-2, BAX, and caspase-3 [71]; ACTA2 [72,73] |
Overexpression results in dysregulated glycolysis, leading to altered bioenergetics characterized by increased aerobic glycolysis (Warburg effect), thereby promoting cancer cell growth, proliferation, and invasion. |
| Tricarboxylic acid cycle | IDH1/2 | TET2 [74]; JMJD2A [75] | Mutations lead to altered enzyme function, promoting the production of 2-hydroxyglutarate (2HG) which inhibits enzymes that cause differentiation in hematopoietic cells and histone methylation. |
Abbreviations: Myelocytomatosis oncogene (Myc); glucose transporter type 2 (GLUT2); Hexokinase 2 (HK2); Phosphofructokinase (PFK); Lactate Dehydrogenase (LDH); Monocarboxylate Transporter 1 (MCT1); Solute Carrier Family 1 Member 5 (SLC1A5); Solute Carrier Family 7 Member 5 (SLC7A5); Solute Carrier Family 38 Member 5 (SLC38A5); glutaminase (GLS); Glutamate Dehydrogenase (GLUD); glucose-6-phosphate dehydrogenase (G6PD); Transketolase (TKT); TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR); Pyruvate Dehydrogenase (PDH); Carnitine Palmitoyltransferase 1 (CPT1); Lipid Phosphatase and Proteins Phosphatase 1 (LPIN1); Phosphatase and Tensin Homolog (PTEN); Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT); Rat Sarcoma (Ras); mammalian target of rapamycin (mTOR); Rapidly Accelerated Fibrosarcoma/Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase (RAF/MEK/ERK); Phosphoinositide 3-Kinase Catalytic Subunit Alpha (PIK3CA); Epidermal Growth Factor Receptor (EGFR); Pyruvate Dehydrogenase Kinase 1 (PDK1); Pyruvate Dehydrogenase Complex (PDHC); Neurofibromin 1 (NF1); Hypoxia-Inducible Factor 1 Alpha (HIF-1α); Lactate Dehydrogenase A (LDHA); Tuberous Sclerosis Complex 2 (TSC2); Ras Homolog Enriched in Brain (Rheb); Sirtuin 1 (SIRT1); Yes-Associated Protein/Transcriptional Coactivator with PDZ-Motif (YAP/TAZ); Phosphofructokinase Fructose-Bisphosphatase 3 (PFKFB3); Glutamate Oxidotransferase 1 (GOT1); Phosphoserine Aminotransferase 1 (PSAT1); Liver Kinase B1 (LKB1); AMP-Activated Protein Kinase 1/2 (AMPK 1/2); Microtubule Affinity-Regulating Kinase 1/2/3/4 (MARK 1/2/3/4); Salt-Inducible Kinase 1/2/3 (SIK 1/2/3); NUAK Family Kinase 1/2 (NUAK 1/2); Serine/Threonine/NORE1-Related Kinase (SNRK); Fumarate Hydratase (FH); Pyruvate Dehydrogenase Alpha 1 (PDHA1); Phosphoglycerate Mutase 1 (PGAM1); B-cell lymphoma 2 (BCL-2); Bcl-2-Associated X Protein (BAX); Alpha-Smooth Muscle Actin (ACTA2); Isocitrate Dehydrogenase 1/2 (IDH1/2); Tet Methylcytosine Dioxygenase 2 (TET2); Jumonji Domain-Containing 2A (JMJD2A).