Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans

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Scott , T A , Quintaneiro , L M , Norvaisas , P , Lui , P P , Wilson , M P , Leung , K-Y , Herrera-Dominguez , L , Sudiwala , S , Pessia , A , Clayton , P T , Bryson , K , Velagapudi , V , Mills , P B , Typas , A , Greene , N D E & Cabreiro , F 2017 , ' Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans ' , Cell , vol. 169 , no. 3 , pp. 442-+ . https://doi.org/10.1016/j.cell.2017.03.040

Title: Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans
Author: Scott, Timothy A.; Quintaneiro, Leonor M.; Norvaisas, Povilas; Lui, Prudence P.; Wilson, Matthew P.; Leung, Kit-Yi; Herrera-Dominguez, Lucia; Sudiwala, Sonia; Pessia, Alberto; Clayton, Peter T.; Bryson, Kevin; Velagapudi, Vidya; Mills, Philippa B.; Typas, Athanasios; Greene, Nicholas D. E.; Cabreiro, Filipe
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2017-04-20
Language: eng
Number of pages: 33
Belongs to series: Cell
ISSN: 0092-8674
URI: http://hdl.handle.net/10138/183442
Abstract: Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B-6, B-9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease.
Subject: ONE-CARBON METABOLISM
ESCHERICHIA-COLI
CAENORHABDITIS-ELEGANS
DNTP POOLS
5-FLUOROURACIL
AUTOPHAGY
DEFECTS
THERAPY
GLYCINE
CELLS
1182 Biochemistry, cell and molecular biology
3111 Biomedicine
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