Targeting One Carbon Metabolism with an Antimetabolite Disrupts Pyrimidine Homeostasis and Induces Nucleotide Overflow.
Published
Journal Article
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.
Full Text
Duke Authors
Cited Authors
- Ser, Z; Gao, X; Johnson, C; Mehrmohamadi, M; Liu, X; Li, S; Locasale, JW
Published Date
- June 14, 2016
Published In
Volume / Issue
- 15 / 11
Start / End Page
- 2367 - 2376
PubMed ID
- 27264180
Pubmed Central ID
- 27264180
Electronic International Standard Serial Number (EISSN)
- 2211-1247
Digital Object Identifier (DOI)
- 10.1016/j.celrep.2016.05.035
Language
- eng
Conference Location
- United States