Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway

Mona Hoseini Soflaee, Rushendhiran Kesavan, Umakant Sahu, Alpaslan Tasdogan, Elodie Villa, Zied Djabari, Feng Cai, Diem H. Tran, Hieu S. Vu, Eunus S. Ali, Halie Rion, Brendan P. O’Hara, Sherwin Kelekar, James Hughes Hallett, Misty Martin, Thomas P. Mathews, Peng Gao, John M. Asara, Brendan D. Manning (), Issam Ben-Sahra () and Gerta Hoxhaj ()
Additional contact information
Mona Hoseini Soflaee: University of Texas Southwestern Medical Center
Rushendhiran Kesavan: University of Texas Southwestern Medical Center
Umakant Sahu: Feinberg School of Medicine, Northwestern University
Alpaslan Tasdogan: University Hospital Essen & German Cancer Consortium, Partner Site
Elodie Villa: Feinberg School of Medicine, Northwestern University
Zied Djabari: Feinberg School of Medicine, Northwestern University
Feng Cai: University of Texas Southwestern Medical Center
Diem H. Tran: University of Texas Southwestern Medical Center
Hieu S. Vu: University of Texas Southwestern Medical Center
Eunus S. Ali: Feinberg School of Medicine, Northwestern University
Halie Rion: University of Texas Southwestern Medical Center
Brendan P. O’Hara: Feinberg School of Medicine, Northwestern University
Sherwin Kelekar: University of Texas Southwestern Medical Center
James Hughes Hallett: Harvard T. H. Chan School of Public Health
Misty Martin: University of Texas Southwestern Medical Center
Thomas P. Mathews: University of Texas Southwestern Medical Center
Peng Gao: Metabolomics Core Facility, Robert H. Lurie Comprehensive Cancer Center, Northwestern University
John M. Asara: Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School
Brendan D. Manning: Harvard T. H. Chan School of Public Health
Issam Ben-Sahra: Feinberg School of Medicine, Northwestern University
Gerta Hoxhaj: University of Texas Southwestern Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.

Date: 2022
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DOI: 10.1038/s41467-022-30362-z

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