Sweet Tooth of Cancer
How Targeting Tumor Glycolysis is Revolutionizing Cancer Therapy
Introduction: The Warburg Effect—Cancer's Metabolic Masterstroke
In 1924, Otto Warburg observed a paradox: cancer cells voraciously consume glucose without oxygen, producing lactate even in oxygen-rich environments. This "Warburg effect" defies conventional metabolism, where cells fully oxidize glucose via mitochondria. A century later, this metabolic quirk is a bullseye for cancer therapy. With tumors draining glucose reserves—visible on PET scans as glowing "hot spots"—researchers now exploit glycolysis to starve cancers, overcome drug resistance, and remodel the tumor microenvironment 1 8 . For aggressive cancers like colorectal cancer (CRC) and triple-negative breast cancer (TNBC), glycolysis inhibitors are emerging as lifelines.
Illustration of cancer cell metabolism (Credit: Science Photo Library)
The Glycolytic Surge: Why Cancer Cells Crave Sugar
Metabolic Reprogramming 101
Normal cells process glucose in mitochondria for maximal ATP (36 ATP/glucose). Cancer cells opt for glycolysis in the cytoplasm, yielding just 2 ATP/glucose but generating:
- Building blocks (nucleotides, lipids)
- Redox buffers (NADPH)
- Lactate—acidifying the microenvironment to suppress immunity 1 3 .
Key glycolytic enzymes hijacked in cancer:
| Enzyme | Role in Cancer | Therapeutic Target |
|---|---|---|
| HK2 | Phosphorylates glucose; blocks apoptosis | 2-DG, kaempferol |
| PKM2 | Shifts glucose to biomass; promotes metastasis | Shikonin |
| LDHA | Converts pyruvate to lactate; fuels acidity | Oxamate |
| GLUT1 | Glucose transporter; upregulated by HIF-1α | Flavonoids |
The Reverse Warburg Effect
Recent work reveals tumors manipulate their surroundings. Cancer-associated fibroblasts (CAFs) are forced into glycolysis by tumor-derived ROS. CAFs then export lactate, ketones, and fatty acids to feed cancer cells—a metabolic symbiosis enabling tumor growth and therapy resistance 1 .
Comparison of glycolytic flux in normal cells versus cancer cells. Hover over points for details.
Featured Experiment: Hsa_circ_0001756—A Circular RNA Driving Gastric Cancer Glycolysis
A 2025 study identified hsa_circ_0001756, a circular RNA upregulated in gastric cancer (GC), as a potential glycolysis regulator. Could silencing this RNA starve tumors? 2
Methodology: Step-by-Step
- Analyzed 74 GC patient tissues vs. adjacent normal tissue.
- Measured hsa_circ_0001756 via qRT-PCR and correlated levels with tumor stage/size.
- Silencing: Used siRNA to knock down hsa_circ_0001756 in GC cell lines (MKN-45, HGC-27).
- Overexpression: Engineered plasmids to boost hsa_circ_0001756 in GES-1 normal gastric cells.
- RNase R Treatment: Confirmed circular RNA resistance to degradation.
- Pulldown Assays: Identified binding partners (miR-185-3p, PTBP1 protein).
- Actinomycin D Test: Assessed RNA stability after transcriptional blockade.
- Western Blotting: Quantified PGK1, HK2, and LDHA protein levels.
Results & Analysis
- Hsa_circ_0001756 was 3.5-fold higher in GC tissues vs. normal (p < 0.001) and linked to tumor size (Table 1).
- Silencing reduced GC cell proliferation by 60% and migration by 45% (p < 0.01).
- Hsa_circ_0001756 bound PTBP1 to stabilize PGK1 mRNA while sponging miR-185-3p, lifting its brake on PGK1 (Table 2).
| Patient Group | Tumor Size (cm) | hsa_circ_0001756 Level | 5-Yr Survival |
|---|---|---|---|
| Low expression (n=37) | 3.2 ± 0.8 | 1.0 (reference) | 68% |
| High expression (n=37) | 5.6 ± 1.2 | 3.5 ± 0.6* | 29% |
| Enzyme | Change (vs. Control) | Function Impacted |
|---|---|---|
| PGK1 | ↓ 70% | Glucose → Pyruvate |
| LDHA | ↓ 45% | Pyruvate → Lactate |
| HK2 | ↓ 30% | Glucose Uptake |
Significance: This circular RNA is a dual-threat—elevating a key glycolytic enzyme (PGK1) via RNA-protein and RNA-miRNA axes. Targeting it disrupts GC's metabolic engine.
The Scientist's Toolkit: Key Reagents in Glycolysis Research
| Reagent | Function | Example Use |
|---|---|---|
| 2-DG | Competitive HK2 inhibitor | Blocks glucose phosphorylation; in Phase II trials for TNBC 9 |
| Shikonin | Natural LDHA inhibitor | Suppresses lactate production; shrinks tumors in DMBA-induced TNBC models 9 |
| Kaempferol | PKM2 binder (dimer form) | Shifts metabolism to OXPHOS; synergizes with cisplatin 6 9 |
| siRNA-circRNAs | Silences circular RNAs | Blocks hsa_circ_0001756 in gastric cancer 2 |
| 18F-FDG | Radiolabeled glucose analog | PET imaging agent for tumor detection 1 |
2-Deoxyglucose
A glucose analog that inhibits hexokinase, the first enzyme in glycolysis.
Shikonin
Natural compound that inhibits lactate dehydrogenase A (LDHA).
Kaempferol
Flavonoid that binds to PKM2, shifting cancer metabolism.
Therapeutic Frontiers: From Bench to Bedside
FDG-PET/CT scans leverage glucose hunger to locate tumors. In CRC, metabolic signatures predict drug resistance 1 .
TNBC tumors resistant to chemo showed 4-fold higher LDHA vs. sensitive ones. Combining oxamate (LDHAi) with doxorubicin restored drug efficacy in mice 9 .
- Toxicity: Glycolysis inhibitors risk harming highly glycolytic normal cells (neurons, erythrocytes) 1 .
- Metabolic Plasticity: Tumors switch to OXPHOS when glycolysis is blocked—requiring multi-target drugs .
| Drug | Target | Phase | Cancer Type |
|---|---|---|---|
| 2-Deoxyglucose | HK2 | II | TNBC, Glioblastoma |
| CPI-613 (Devimistat) | PDH, α-KGDH | III | Pancreatic, AML |
| FX11 | LDHA | I/II | Various solid tumors |
Conclusion: A Metabolic Revolution in Oncology
Targeting tumor glycolysis has evolved from Warburg's curiosity to a pillar of precision oncology. With circular RNAs like hsa_circ_0001756 revealing new targets, and natural compounds like shikonin entering trials, we're poised to starve cancers of their sweet advantage. As research tackles metabolic heterogeneity and toxicity, glycolytic inhibitors may soon join chemotherapy and immunotherapy as standard arms in our anti-cancer arsenal 1 6 9 .
"Cancer is a metabolic disease. If we control the fuel, we control the fire."