Targeting One Carbon Metabolism with an Antimetabolite Disrupts Pyrimidine Homeostasis and Induces Nucleotide Overflow.
Antimetabolites that affect nucleotide metabolism are frontline chemotherapy agents in several cancers and often successfully target one carbon metabolism. However, the precise mechanisms and resulting determinants of their therapeutic value are unknown. We show that 5-fluorouracil (5-FU), a commonly used antimetabolite therapeutic with varying efficacy, induces specific alterations to nucleotide metabolism by disrupting pyrimidine homeostasis. An integrative metabolomics analysis of the cellular response to 5-FU reveals intracellular uracil accumulation, whereas deoxyuridine levels exhibited increased flux into the extracellular space, resulting in an induction of overflow metabolism. Subsequent analysis from mice bearing colorectal tumors treated with 5-FU show specific secretion of metabolites in tumor-bearing mice into serum that results from alterations in nucleotide flux and reduction in overflow metabolism. Together, these findings identify a determinant of an antimetabolite response that may be exploited to more precisely define the tumors that could respond to targeting cancer metabolism.
Tri-Institutional Training Program in Chemical Biology, Weill Cornell Medical College, Rockefeller University, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Zheng
Z
Ser
Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Xia
X
Gao
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Christelle
C
Johnson
Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA; Graduate Field of Genetics Genomics and Development, Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Mahya
M
Mehrmohamadi
Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Xiaojing
X
Liu
Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
Siqi
S
Li
Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: jason.locasale@duke.edu.
Jason W
JW
Locasale
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002244:Carbon / Q000378:metabolism*; D045744:Cell Line, Tumor; D005472:Fluorouracil / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009711:Nucleotides / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D009711:Nucleotides; D011743:Pyrimidines; D002244:Carbon; C030986:pyrimidine; D005472:Fluorouracil