Abstract：
: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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Ser Z,Gao X,Johnson C,Mehrmohamadi M,Liu X,Li S,Locasale JWdoi
10.1016/j.celrep.2016.05.035subject
Has Abstractpub_date
2016-06-14 00:00:00pages
2367-76issue
11issn
2211-1247pii
S2211-1247(16)30618-0journal_volume
15pub_type
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