Altered metabolite levels in cancer: implications for tumour biology and cancer therapy

• Focus: This review examines how altered intracellular metabolite concentrations in cancer cells, often driven by genetic mutations, actively promote tumor initiation and progression, moving beyond the idea that metabolic changes are merely a consequence of cancer.
• Oncometabolites: Specific metabolites act as effector molecules:
  • 2-Hydroxyglutarate (2-HG): Produced by IDH1/2 mutations, it inhibits epigenetic regulators (like TET enzymes) leading to globally altered gene expression and oncogenesis.
  • Fumarate and Succinate: Accumulate due to FH/SDH mutations, leading to the stabilization of HIF-\(1\alpha\) (pseudohypoxia), which drives proliferation and the Warburg effect.
• Implication: The altered metabolome is a rich source of therapeutic targets. Strategies can focus on counteracting the effects of oncometabolites or exploiting the metabolic dependencies created by these shifts (e.g., limited aspartate for nucleotide synthesis).

PubMed: 27658530 DOI: 10.1038/nrc.2016.85 Overview generated by: Gemini 2.5 Flash, 28/11/2025

Key Focus: Metabolite Concentration as a Driver of Cancer Biology

This review explores how altered intracellular metabolite concentrations—a fundamental characteristic of cancer cells (metabolic reprogramming)—can actively promote tumor initiation, progression, and survival, rather than merely being a consequence of altered metabolism.

The Oncogenic Role of Metabolites

The core concept is that changes in the concentration of specific metabolites, often driven by genetic mutations or cancer-associated protein modifications, can act as oncometabolites or signaling molecules. These altered levels can then directly impact cell fate by modifying proteins, regulating gene expression, and altering redox balance.

Major Oncometabolites and Their Mechanisms

The review details several key metabolites whose altered levels have profound implications for cancer:

1. 2-Hydroxyglutarate (2-HG)

• Source: Produced at high levels by mutations in Isocitrate Dehydrogenase 1 (IDH1) or IDH2.
• Mechanism: 2-HG is an “oncometabolite” that functions as a potent competitive inhibitor of several \(\alpha\)-ketoglutarate (\(\alpha\)-KG)-dependent dioxygenases, including epigenetic regulators like TET DNA demethylases and histone demethylases.
• Effect: This inhibition leads to a hypermethylation phenotype and globally altered gene expression, promoting oncogenesis.

2. Fumarate and Succinate

• Source: Accumulate due to mutations in the tricarboxylic acid (TCA) cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH).
• Mechanism: Similar to 2-HG, these two metabolites are also \(\alpha\)-KG competitive inhibitors. They inhibit \(\alpha\)-KG-dependent prolyl hydroxylase (PHD) enzymes.
• Effect: Inhibition of PHDs stabilizes the transcription factor Hypoxia-Inducible Factor 1\(\alpha\) (HIF-\(1\alpha\)). This leads to the activation of the Warburg effect and promotes cell proliferation and angiogenesis, even in normoxic conditions (pseudohypoxia).

3. Aspartate

• Source: Can be limited in tumor environments, leading to reduced cell proliferation.
• Effect: Aspartate is a critical precursor for the synthesis of nucleotides (purines and pyrimidines). Its availability links the rate of mitochondrial metabolism (TCA cycle) directly to cell proliferation, acting as a metabolic checkpoint.

4. Reactive Oxygen Species (ROS)

• Source: Increased ROS production due to altered mitochondrial function and high metabolic flux.
• Dual Role: While high ROS levels can induce cell death, moderate, sustained increases in ROS can promote tumorigenesis by activating pro-survival signaling pathways and contributing to DNA damage.

Therapeutic Implications

Understanding the altered metabolome provides clear therapeutic vulnerabilities:

• Targeting Metabolite Effects: Drugs can be developed to counteract the downstream effects of oncometabolites (e.g., targeting the epigenetic readers or writers whose activity is modified by 2-HG).
• Exploiting Dependencies: Cancer cells often become dependent on specific nutrients or pathways due to metabolic constraints (e.g., relying on external aspartate). Inhibiting the transport or synthesis of these essential metabolites could selectively kill tumor cells.

Conclusion

The review concludes that changes in intracellular metabolite concentrations are a central feature of cancer cell biology, acting as effector molecules that dictate cancer phenotype. Metabolomics is thus vital for identifying new therapeutic targets and understanding the underlying mechanisms of malignancy.