Insights into Metabolic Reprogramming in Tumor Evolution and Therapy

Abstract

Background: Cancer remains a global health challenge, characterized not just by uncontrolled cell proliferation but also by the complex metabolic reprogramming that underlies its development and progression. Objectives: This review delves into the intricate relationship between cancer and its metabolic alterations, drawing an innovative comparison with the cosmological concepts of dark matter and dark energy to highlight the pivotal yet often overlooked role of metabolic reprogramming in tumor evolution. Methods: It scrutinizes the Warburg effect and other metabolic adaptations, such as shifts in lipid synthesis, amino acid turnover, and mitochondrial function, driven by mutations in key regulatory genes. Results: This review emphasizes the significance of targeting these metabolic pathways for therapeutic intervention, outlining the potential to disrupt cancer's energy supply and signaling mechanisms. It calls for an interdisciplinary research approach to fully understand and exploit the intricacies of cancer metabolism, pointing toward metabolic reprogramming as a promising frontier for developing more effective cancer treatments. Conclusion: By equating cancer's metabolic complexity with the enigmatic nature of dark matter and energy, this review underscores the critical need for innovative strategies in oncology, highlighting the importance of unveiling and targeting the "dark energy" within cancer cells to revolutionize future therapy and research.

Keywords: Warburg effect; cancer; metabolic reprogramming.

Figure 1

A comparison of the major metabolic pathways in (A) normal and (B) cancer cells. In normal cells (A), glucose enters via GLUT transporters, fueling glycolysis and predominantly generating ATP through oxidative phosphorylation (OXPHOS) in the mitochondria. Fatty acid oxidation and glutaminolysis also contribute to ATP production and lipid synthesis. Pathways with relatively low activity, such as lactate production, are indicated by dashed lines. In contrast, cancer cells (B) demonstrate increased glucose uptake via upregulated GLUT transporters, resulting in enhanced glycolysis and the Warburg effect, where pyruvate is converted to lactate even in the presence of oxygen. This metabolic reprogramming supports rapid ATP production and proliferation. Despite the dominance of the Warburg effect, minimal TCA cycle activity and OXPHOS are retained, as indicated by the dashed lines. Abbreviations: glucose transporter type 1 (GLUT1); Monocarboxylate Transporter (MCT); adenosine triphosphate (ATP); mammalian target of rapamycin (mTOR); α-Ketoglutarate (α-KG); branched-chain amino acids (BCAAs); Solute Carrier Family 7 Member 5 (SLC7A5); Solute Carrier Family 1 Member 5 (SLC1A5); Fatty Acid Transport Protein (FATP); Plasma Membrane Fatty Acid-Binding Protein (FABPpm).

Figure 2

An overview of the major metabolic pathways at work within cancer cells. Cell survival, growth, and proliferation require glucose to generate ATP, lipids, and amino acids through glycolysis, alongside other downstream reactions and pathways, including the pentose phosphate pathway, glutaminolysis, lipid synthesis, and branched-chain amino acid (BCAA) metabolism. The Warburg effect, characterized by increased glucose uptake and lactate production despite adequate oxygen, highlights metabolic reprogramming, supporting rapid tumor growth and survival even under oxidative conditions. The mTOR signaling pathway regulates cell growth, proliferation, survival, and cytoskeletal organization in response to insulin, growth factors, and other metabolic and cellular cues. Additionally, p53 plays an important role in promoting ATP production, facilitating citric acid cycle (also referred to as the TCA cycle or Krebs cycle) and glutamate synthesis, while regulating glycolysis and lipid synthesis. Dysregulation of mTOR signaling and p53 has been implicated in numerous diseases, including cancer and metabolic disorders. Moreover, the metabolic processes of cancer cells operate in distinct ways depending on the availability of nutrients. In situations where nutrients are abundant (nutrient-replete conditions), there is a focus on nucleotide production, lipid generation, and the utilization of glutamine. Conversely, under nutrient-deprived conditions, cancer cells favor fatty acid oxidation, acetate breakdown, the utilization of BCAAs, and glutaminolysis related to macropinocytosis and autophagy. Understanding the metabolic adaptations of cancer cells to diverse nutrient environmental conditions is vital for developing targeted therapies to combat disease progression. Abbreviations: Pentose phosphate pathway. glucose-6-phosphate dehydrogenase (G6PD); Ribulose 5-phosphate (Ribulose-5P); Xylulose 5-phosphate (Xylulose-5P); Ribose 5-phosphate (Ribose-5P); Glyceraldehyde 3-phosphate (G3P); Sedoheptulose 7-phosphate (sedoheptulose-7P); Transaldolase (TALDO); Erythrose 4-phosphate (Erythrose-4P); Fructose 6-phosphate (Fructose 6-p). Glycolysis. glucose-6-phosphate dehydrogenase (G6PD); Fructose 6-phosphate (Fructose 6-p); Fructose 1,6-biphosphate (Fructose 1,6-biP); Fructose 2,6-biphosphate (Fructose 2,6-biP); Glyceraldehyde 3-phosphate (GA3P); Dihydroxyacetone phosphate (DHAP); Glyceraldehyde-3-phosphate dehydrogenase (GAPDH); Phosphoglycerate mutase (PGAM); Pyruvate kinase M2 (PKM2); Lactate dehydrogenase (LDH). mTOR pathway. Phosphatidylinositol-3 kinase (PI3K); Protein kinase B (AKT); Rat sarcoma (Ras); Rapidly Accelerated Fibrosarcoma (Raf); Mitogen-Activated Protein Kinase (MEK); Extracellular Signal-Regulated Kinase (ERK); p90 Ribosomal S6 Kinase (RSK); Tuberous Sclerosis Complex1/2 (TSC1/2); Ras Homolog Enriched in Brain (Rheb); Guanosine Triphosphate (GTP); Ras-related GTP binding A/B (Rag A/B); Ras-related GTP binding C/D (Rag C/D); Guanosine Diphosphate (GDP); mammalian target of rapamycin (mTOR); Hypoxia-Inducible Factor 1 (HIF-1). branched-chain amino acid (BCAA). α-ketoglutarate (α-KG); glutamine (Gln); glutamate (Glu); Branched-chain Aminotransferases (BCAT); 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA); α-ketoisocaproate (KIC); branched-chain amino acid Aminotransferase (BCAT). Glutaminolysis. glutaminase (GLS); Glutamate Dehydrogenase (GLUD); Sodium-Dependent Neutral Amino Acid Transporter (SLC1A5). Lipid Synthesis. 3-hydroxyl3-methyl-glutaryl-coenzyme A reductase (HMG-CoA); Acetyl-CoA Carboxylase (ACACA); fatty acid synthase (FASN); 3-hydroxy-3-methylglutaryl-CoA Reductase (HMGCR); Farnesyl Pyrophosphate (FPP); Stearoyl-Coa Desaturase (SCD); Monounsaturated Fatty Acid (MUFA); Polyunsaturated Fatty Acid (PUFA).