Proline Metabolism in Cancer Biology

Proline, a non-essential amino acid, occupies a central position in tumour cell metabolism, acting both as a building block for protein and as a regulator of redox balance and energy homeostasis. In cancer cells, the pathways governing proline synthesis and degradation are frequently reprogrammed to meet heightened biosynthetic and bioenergetic demands. Enhanced activity of pyrroline-5-carboxylate reductase enzymes drives proline production from glutamine and supports nucleotide and protein synthesis, while proline catabolism via proline dehydrogenase contributes to adenosine triphosphate generation and reactive oxygen species signalling. Beyond intrinsic tumour cell functions, proline metabolism shapes the surrounding microenvironment by facilitating collagen deposition in cancer-associated fibroblasts and modulating cytokine release, thereby influencing extracellular matrix remodelling, immune evasion and metastatic dissemination. The dual roles of proline in cellular biosynthesis and stress adaptation render its metabolic circuit a promising target for therapeutic intervention, with strategies aimed at inhibiting key enzymes or disrupting the proline cycle showing potential to suppress tumour growth, stem-like cell maintenance and metastatic colonisation.

Research from Nature Portfolio

Recent studies have elucidated a hypoxia-responsive mechanism in which nuclear insulin-like growth factor receptor phosphorylates pyrroline-5-carboxylate reductase 1 (PYCR1), enhancing its recruitment to transcriptional regulators and sustaining colorectal tumour growth under low-oxygen conditions. Investigations into mitochondrial cofactor dynamics have revealed that mitochondrial NADP+ levels, maintained by NAD kinase 2 activity, are indispensable for proline biosynthesis and subsequent cell proliferation, highlighting a metabolic vulnerability in cancer cells lacking this pool. Foundational work on proline catabolism demonstrated that enhanced expression of proline dehydrogenase supports invasive growth and lung metastasis formation in breast cancer models, and that pharmacological inhibition of this enzyme effectively impairs metastatic outgrowth without significant toxicity to normal tissues.

Proline Metabolism in Cancer Biology publication trend

The graph below shows the total number of articles in proline metabolism in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Pyrroline-5-carboxylate reductase (PYCR1): Enzyme catalysing the NADPH-dependent conversion of pyrroline-5-carboxylate into proline, often overexpressed in tumours to support anabolic processes.

Proline dehydrogenase (PRODH): Mitochondrial enzyme initiating the oxidative breakdown of proline, linking its catabolism to energy production and reactive oxygen species signalling.

Tumour microenvironment (TME): The composite of non-malignant cells, extracellular matrix and soluble factors surrounding cancer cells, which influences tumour growth, invasion and immune response.

cGMP-PKG signalling: Intracellular pathway activated by cyclic guanosine monophosphate binding to protein kinase G, implicated in mediating proline-driven maintenance of cancer stem-like phenotypes.

Mitochondrial NADP(H): The pool of reduced nicotinamide adenine dinucleotide phosphate within mitochondria, providing reducing equivalents for biosynthetic reactions including proline synthesis.

References

1. IGF1R-phosphorylated PYCR1 facilitates ELK4 transcriptional activity and sustains tumor growth under hypoxia. Nature Communications (2023).
2. Mitochondrial NADP+ is essential for proline biosynthesis during cell growth. Nature Metabolism (2021).
3. Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells. Nature Communications (2017).
4. Pyrroline-5-carboxylate reductase 1 reprograms proline metabolism to drive breast cancer stemness under psychological stress. Cell Death & Disease (2023).
5. Proline metabolism shapes the tumor microenvironment: from collagen deposition to immune evasion. Current Opinion in Biotechnology (2023).
6. Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer. Molecular Metabolism (2024).