Purine nucleotides are essential for cell growth and function as they serve as nucleic acid building blocks, signaling molecules, and energy carriers. Treatments that inhibit their synthesis offer a powerful strategy to hinder cancer cell growth, but patients may sometimes develop resistance to these drugs. Researchers hope that a better understanding of the purine production pipeline will lead to the development of novel treatments.
In a recent study published in Cell, researchers reported that tumor cells in mice may recover circulating molecules to maintain their purine pools.1 Furthermore, the authors found that feeding the animals a nucleotide-rich diet accelerated tumor growth. The findings could help refine cancer therapies that target nucleotide metabolism and guide dietary recommendations for patients with cancer.
Cells sustain their purine levels through two pathways: De novo synthesis builds purines from scratch, whereas the salvaging route uses intermediate metabolites, such as those obtained from the diet. While the prevailing assumption in the field is that proliferating cells, including cancer cells, mostly rely on de novo synthesis to maintain their purine supply, no studies had explored this question in vivo.2
Gerta Hoxhaj, a cancer metabolism researcher at the Children’s Medical Center Research Institute at the University of Texas Southwestern, led a team of researchers to tackle this challenge. They tracked purine production across six mouse cancer models, including xenograft breast and colon tumors. They infused the mice with tagged nutrients that fed either the de novo or the salvage pathway. By tracing how these molecules contributed to new purines, they determined the cells’ dependence on each pathway. Although the contribution varied by cancer type and nutrient, they found that both production routes played significant and similar roles in supplying the tumors’ purine pools.
To further assess the significance of each pathway in cancer cell proliferation, Hoxhaj and her colleagues used CRISPR-Cas9 or RNA interference to knock out a key enzyme in the de novo pathway or one of the two enzymes in charge of the salvage pathway. Disrupting the de novo pathway prevented tumor formation or slowed down tumor progression depending on the cancer type, confirming the fundamental role of this route in cancer cell proliferation.3 Similarly, a deficiency of either enzyme involved in metabolite salvage reduced tumor growth, although the effects were smaller than those produced through interfering with the de novo pathway.
“The fact that loss of the salvage pathway in tumors seems to restrict tumor growth…is quite surprising,” said Kasper Fugger, a cancer cell biologist at University College London who did not participate in the study. Yet, he wondered whether, over time, de novo synthesis would ramp up to compensate for the reduction in purine production.
It could, Hoxhaj acknowledged. One reason cancer is so difficult to eradicate is its metabolic flexibility, she said. Her findings suggest that the salvage pathway could be an access route for cancer cells to get their nucleotide supply when chemotherapeutic drugs inhibit the de novo pathway. But along the same lines, cells could also adapt to the loss of the salvage pathway. Her team is now exploring how the two pathways communicate with each other with the hopes of developing therapeutic strategies that make cancer cells less efficient at switching between the de novo and the salvage pathways for supplying their purines.
Since dietary nucleotides are a potential source of purines for the salvage pathway, Hoxhaj’s team wondered whether supplementing mice with nucleotides could impact tumor growth. They fed tumor-bearing mice a nucleotide mixture that was equivalent to two to three steaks a day for a human. “Maybe it is a little bit too much,” Hoxhaj acknowledged, but the idea was to test whether nucleotide availability could impact growth. The findings suggested they did: After several weeks, the nucleotide-rich diet led to bigger tumors.
The contribution of dietary nucleotides to tumor growth is an important finding that scientists hadn’t previously considered, said Fugger. He and Hoxhaj both said that it’s worth exploring whether a low-nucleotide diet could benefit patients with cancer who are undergoing specific treatments. “Food matters,” said Hoxhaj, and so does how much access the tumors have to nucleotides as a nutrient source.
- Tran DH, et al. De novo and salvage purine synthesis pathways across tissues and tumors. Cell. 2024;187(14):3602-3618.e20.
- Ali ES, Ben-Sahra I. Regulation of nucleotide metabolism in cancers and immune disorders. Trends Cell Biol. 2023;33(11):950-966.
- Villa E, et al. Cancer cells tune the signaling pathways to empower de novo synthesis of nucleotides. Cancers. 2019;11(5):688.
