4.Cancer Metabolism

(Integrated explanation + mechanisms + clinical relevance)

1. Warburg Effect – Core Concept

Cancer cells preferentially use aerobic glycolysis:

• ↑ Glucose uptake
• Convert glucose → lactate, even when O2 present
• ATP yield low (≈2–4 ATP/glucose)
• First described by Otto Warburg
• Basis for PET imaging (18F-FDG uptake)

Why choose glycolysis if inefficient?

Because tumor cells value biosynthesis > energy:

• Glycolysis intermediates diverted into nucleotide + amino acid + lipid synthesis
• Supports rapid biomass accumulation
• Fast ATP delivery despite low yield

Do mitochondria shut down?

No.

• Mitochondria remain active
• Supply biosynthetic precursors:
• Citrate → acetyl-CoA → lipids
• TCA cycle intermediates for anabolism
• OXPHOS reduced rather than absent

2. Molecular Triggers & Signaling Reprogramming

Growth factor pathways → metabolic shift to anabolic state.

Oncogenes promoting glycolysis

• RAS
• ↑ glucose transporters
• ↑ glycolytic enzymes
• ↑ lipid synthesis
• ↑ protein synthesis
• MYC
• ↑ glycolytic gene expression
• ↑ glutaminase → glutamine carbon used for biosynthesis

Key metabolic switch

↓ Pyruvate kinase activity → causes intermediate buildup → diverted into synthetic pathways.

Tumor suppressors opposing Warburg metabolism

• NF1 / PTEN
• Inhibit growth factor signaling
• p53
• ↓ glucose uptake
• ↓ glycolysis
• ↓ lipogenesis
• ↓ NADPH production

Loss → metabolism locked into constant growth mode.

3. Autophagy in Cancer

Definition

Survival response during nutrient stress:

• Growth arrest
• Lysosomal degradation of organelles + proteins
• Recycles building blocks + energy

Consequences of failure

• Cells unable to adapt → death

Dual role in cancer

Tumor-suppressive:

• Removes damaged organelles/proteins
• Prevents ROS and DNA damage accumulation

Tumor-promoting:

• Allows cancer cells to survive metabolic stress
• Maintains dormancy under therapy → contributes to relapse

Genetic link

Many tumor suppressor proteins stimulate autophagy.

Loss → pathway defective → survival advantage.

4. Tumor Dormancy

State of minimal metabolic activity + non-proliferation.

• Autophagy enables cells to “hibernate”
• Not targeted by drugs attacking dividing cells
• Clinical consequence → recurrence years later

5. Oncometabolism

Altered metabolism due to enzymatic mutations producing abnormal metabolites.

Prototype pathway – IDH1 & IDH2 mutations

Normal:

• Isocitrate → α-ketoglutarate (α-KG)

Mutant gain-of-function:

• α-KG → 2-hydroxyglutarate (2-HG)

2-HG = Oncometabolite

• Inhibits TET2 (DNA demethylation enzyme)
• Results:
• Persistence of methylation marks
• Misregulated gene expression
• Blocks differentiation + promotes oncogenesis

Cancers with IDH mutations

• Gliomas
• Cholangiocarcinoma
• AML
• Some sarcomas

Therapeutic application

• Mutant-specific IDH inhibitors
• Selectively block mutant enzyme
• Spare normal metabolism

6. Integrated Functional Framework

Cancer metabolism reprogramming involves:

7. Exam-ready summary

• Cancer metabolism prioritizes growth and biomass, not ATP efficiency.
• Warburg metabolism ensures maximal precursor availability.
• Autophagy both suppresses and supports tumors.
• Oncometabolites such as 2-HG hijack epigenetic regulation.
• Tumor dormancy is clinically important because it can evade therapy → relapse risk.
• PET scans visualize the Warburg phenomenon via FDG uptake.

🧠 EXAM REFLEX BLOCK — Cancer Metabolism (Zero-Omission, High-Yield)

Lock these lines. If you can reflex-recall them, you won’t miss MCQs or SBAs.

Warburg Effect

• Cancer cells preferentially use aerobic glycolysis → glucose → lactate despite oxygen.
• ATP yield is low, but flux is high and rapid.
• Purpose is biosynthesis, not energy efficiency.
• Mitochondria are functional, but OXPHOS is down-regulated, not absent.
• Basis of 18F-FDG PET scanning.

👉 Exam trap: Warburg ≠ mitochondrial failure.

Why glycolysis is favored

• Glycolytic intermediates feed:
• Pentose phosphate pathway → nucleotides + NADPH
• Amino acid synthesis
• Lipid synthesis
• Reduced pyruvate kinase activity → intermediate buildup → anabolic diversion.

Oncogene-driven metabolic reprogramming

• RAS → ↑ GLUTs, ↑ glycolysis, ↑ lipid & protein synthesis.
• MYC → ↑ glycolytic genes + ↑ glutaminase → glutamine-driven anabolism.

Tumor suppressors (anti-Warburg)

• p53 → ↓ glucose uptake, ↓ glycolysis, ↓ lipogenesis, ↓ NADPH.
• PTEN / NF1 → suppress growth-factor signaling.
• Loss → constitutive anabolic metabolism.

👉 Exam trap: p53 loss = metabolic shift, not just cell-cycle loss.

Autophagy

• Stress-response pathway → lysosomal recycling of organelles/proteins.
• Enables survival during nutrient deprivation, hypoxia, therapy.

Dual role:

• Tumor-suppressive: removes damaged mitochondria → ↓ ROS, ↓ DNA damage.
• Tumor-promoting: supports survival → dormancy + resistance.

Tumor dormancy

• Non-proliferative, low-metabolic state.
• Autophagy-dependent survival.
• Evades chemo/radiotherapy → late relapse.

👉 Exam pearl: Dormant ≠ dead.

Oncometabolism

• Mutant metabolic enzymes generate oncometabolites.

IDH1 / IDH2 mutations

• Normal: isocitrate → α-KG
• Mutant: α-KG → 2-hydroxyglutarate (2-HG)

2-HG effects

• Inhibits α-KG–dependent enzymes (e.g. TET2).
• Causes DNA hypermethylation.
• Blocks differentiation → oncogenesis.

Cancers with IDH mutations

• Gliomas
• AML
• Cholangiocarcinoma
• Some sarcomas

Therapeutic relevance

• Mutant-specific IDH inhibitors:
• Target cancer metabolism
• Spare normal cells
• Metabolism = targetable vulnerability, not just a consequence.

🧷 ONE-LINE EXAM LOCK

Cancer cells reprogram metabolism toward aerobic glycolysis and autophagy-supported survival to maximize biosynthetic precursors, while oncometabolites like 2-HG epigenetically block differentiation, enabling growth, dormancy, and relapse.