104 Cancer Metabolism

Cancer metabolism is characterized by a complex network of reprogrammed pathways that support uncontrolled proliferation and survival. These metabolic adaptations involve shifts in energy production, increased biosynthesis of macromolecules, and dynamic interactions with the tumor microenvironment. Here are the key mechanisms:

1. Aerobic Glycolysis (Warburg Effect)

Cancer cells preferentially use glycolysis for ATP production even in oxygen-rich conditions1 2. This shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regulated by:

Hypoxia-inducible factor 1 (HIF-1) driving glycolytic enzyme expression1.
Oncogenes (Myc, PI3K/Akt/mTOR) upregulating glucose transporters (GLUTs) and enzymes like hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA)1.
Loss of tumor suppressor p53, which normally suppresses glycolysis1.
While less efficient in ATP yield, glycolysis provides rapid energy and intermediates for nucleotides, lipids, and amino acids1.

2. Glutamine Metabolism

Glutamine serves as a critical carbon and nitrogen source for:

TCA cycle anaplerosis via conversion to α-ketoglutarate (α-KG)1 4.
Nucleotide biosynthesis through coordinated shifts in glutaminolysis and PPAT-mediated pathways1.
NADPH production to combat oxidative stress1.

3. Lipid Metabolism

Tumors exhibit:

Increased lipid uptake via CD36 and other transporters.
Enhanced lipogenesis driven by ATP-citrate lyase (ACLY) and fatty acid synthase (FASN)1.
Cholesterol synthesis to support membrane biogenesis1.

4. Pentose Phosphate Pathway (PPP) and One-Carbon Metabolism

PPP supplies NADPH for redox balance and ribose for nucleotides1.
One-carbon metabolism (folate/methionine cycles) generates ATP, NADH/NADPH, and nucleotides, supported by serine/glycine biosynthesis1. Serine biosynthesis enzymes like PHGDH are amplified in breast and prostate cancers1.

5. Amino Acid Reprogramming

Serine biosynthesis from 3-phosphoglycerate (3-PG) is upregulated via PHGDH, PSAT1, and PSPH under metabolic stress1.
Altered methionine metabolism supports methylation reactions and redox homeostasis1.

6. Regulatory Signaling Pathways

Metabolic reprogramming is orchestrated by:

Oncogenic kinases (PI3K/Akt/mTOR) enhancing nutrient uptake and glycolysis3 5.
Transcriptional regulators (c-Myc, HIF-1, Nrf2) activating metabolic genes1 3.
Non-coding RNAs fine-tuning enzyme expression1.

7. Metabolic Plasticity and Microenvironment Interactions

Tumors dynamically adapt to nutrient availability through:

Substrate switching (e.g., lactate or acetate utilization)1.
Reverse Warburg Effect, where stromal cells supply metabolites1.
Crosstalk with immune cells to reshape metabolic niches3.

These interconnected mechanisms enable cancer cells to meet biosynthetic demands while surviving hostile microenvironments. Targeting metabolic vulnerabilities (e.g., PHGDH inhibition or glutamine deprivation) represents a promising therapeutic strategy1 3 5.