کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2038958 | 1072998 | 2016 | 10 صفحه PDF | دانلود رایگان |
• One carbon metabolism fluxes correlate with 5-fluorouracil (5-FU) sensitivity
• 5-FU causes nucleotide imbalance by inhibiting thymidylate synthase
• 5-FU induces overflow metabolism in pyrimidine synthesis
• Alterations in overflow metabolism from colorectal tumors can be measured in serum
SummaryAntimetabolites 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.
Graphical AbstractFigure optionsDownload as PowerPoint slide
Journal: - Volume 15, Issue 11, 14 June 2016, Pages 2367–2376