کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2038958 1072998 2016 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Targeting One Carbon Metabolism with an Antimetabolite Disrupts Pyrimidine Homeostasis and Induces Nucleotide Overflow
ترجمه فارسی عنوان
هدف قرار دادن یک متابولیسم کربن با یک آنتی متابولیت باعث اختلال هومیوستاز پرییمیدین و منجر به سرریز نوکلئوتید
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم کشاورزی و بیولوژیک علوم کشاورزی و بیولوژیک (عمومی)
چکیده انگلیسی


• 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.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 15, Issue 11, 14 June 2016, Pages 2367–2376
نویسندگان
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