Biochemistry of Cancer Metabolism
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Direct answer
Rewiring metabolism is a hallmark of cancer, not a by-product of it. Most tumours ferment glucose to lactate even when oxygen is plentiful — the Warburg effect — trading ATP yield for speed, NADPH and biosynthetic intermediates, which is exactly why FDG-PET lights them up. Beyond glucose, many cancers become addicted to glutamine, feeding glutaminolysis into the citric acid cycle for carbon, nitrogen and redox balance; they ramp up lipogenesis and the pentose phosphate pathway for membrane and nucleotide synthesis; and some carry IDH1/2 mutations that create a genuinely new oncometabolite, 2-hydroxyglutarate, which rewires epigenetics. Growth-factor and oxygen sensing (HIF-1α, PI3K-AKT-mTOR) sits upstream of every one of these switches, so oncogenic signalling and metabolic reprogramming are two descriptions of one process.
What you must remember
- Warburg effect: aerobic glycolysis — high glucose uptake with lactate export through monocarboxylate transporters despite normoxia; two ATP per glucose, but rapid, and coupled to macromolecule synthesis; Otto Warburg described it in the 1920s.
- FDG-PET logic: fluorodeoxyglucose is phosphorylated by hexokinase and then trapped — it cannot leave through GLUT transporters or proceed down glycolysis — so radioactivity accumulates in proportion to glycolytic flux; standard in lymphoma staging in Indian practice.
- HIF-1α: stabilised when prolyl hydroxylation fails in hypoxia; induces GLUT1, glycolytic enzymes and VEGF — the molecular link between hypoxia, glycolysis and angiogenesis.
- Glutaminolysis: glutaminase converts glutamine to glutamate, then α-ketoglutarate; glutamine also supplies amide nitrogen for nucleotides and NADPH through malic enzyme — the basis of glutamine addiction. Asparaginase starves lymphoblasts of asparagine in acute lymphoblastic leukaemia protocols, a metabolic drug disguised as chemotherapy.
- Oncometabolite: mutant IDH1/2 produces D-2-hydroxyglutarate, which inhibits TET2 and histone demethylases, producing the glioma CpG-island methylator phenotype; ivosidenib (IDH1) and enasidenib (IDH2) block this in AML.
- Biosynthetic diversion: tumours express the embryonic PKM2 isoform of pyruvate kinase; glucose carbon flows to serine and glycine (one-carbon pool), ribose (pentose phosphate pathway) and exported citrate for fatty acid synthesis.
- Metformin: activates AMPK and inhibits complex I; observational data suggest outcome benefit in diabetics with cancer, but it is a signal, not proven therapy — quote it that way.
Where students slip
The classic error is equating the Warburg effect with hypoxia: oxygen availability is normal; the point is oxygen-independent glycolysis, and mitochondria remain functional and necessary for citrate, α-ketoglutarate and apoptotic signalling. The second error treats lactate as waste, when it is an exported fuel for oxidative cancer cells and stromal neighbours, shuttled much like the Cori cycle. A reliable viva question asks why mitochondria do not disappear from cancer cells: citric acid cycle intermediates are continuously drawn off for biosynthesis and must be replenished anaplerotically — glutamine and pyruvate carboxylase do that replenishing.
Frequently asked questions
Why do tumours prefer glycolysis despite its low ATP yield?
Glycolysis is rapid, and its intermediates feed the pentose phosphate pathway, serine biosynthesis and lipogenesis — proliferation needs carbon skeletons and NADPH more than maximal ATP.
What is an oncometabolite?
A metabolite made only by a mutant enzyme, such as D-2-hydroxyglutarate from mutant IDH1/2, which alters epigenetics by inhibiting demethylases.
Why is FDG trapped inside tumour cells?
Hexokinase phosphorylates FDG to FDG-6-phosphate, which can neither exit through GLUT transporters nor continue down glycolysis, so the tracer accumulates with glycolytic flux.
How does asparaginase kill lymphoblasts?
Lymphoblasts lack adequate asparagine synthetase, so depleting extracellular asparagine halts their protein synthesis.
Do all cancers show the Warburg effect?
Most show heightened glycolysis, but oxidative phosphorylation persists and even dominates in some tumours — metabolism varies with tumour type and microenvironment.