Thymidylate synthase and dihydropyrimidine dehydrogenase levels are associated with response to 5-fluorouracil in Caenorhabditis elegans.
5-Fluorouracil (5-FU), a pyrimidine antagonist, has a long history in cancer treatment. The targeted pyrimidine biosynthesis pathway includes dihydropyrimidine dehydrogenase (DPD), which converts 5-FU to an inactive metabolite, and thymidylate synthase (TS), which is a major target of 5-FU. Using Caenorhabditis elegans as a model system to study the functional and resistance mechanisms of anti-cancer drugs, we examined these two genes in order to determine the extent of molecular conservation between C. elegans and humans. Overexpression of the worm DPD and TS homologs (DPYD-1 and Y110A7A.4, respectively) suppressed germ cell death following 5-FU exposure. In addition, DPYD-1 depletion by RNAi resulted in 5-FU sensitivity, while treatment with Y110A7A.4 RNAi and 5-FU resulted in similar patterns of embryonic death. Thus, the pathway of 5-FU function appears to be highly conserved between C. elegans and humans at the molecular level.
Kim
Seongseop
S
Cancer Experimental Resources Branch, National Cancer Center, Goyang, Korea.
Park
Dae-Hun
DH
Shim
Jaegal
J
D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047108:Embryonic Development / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D034622:RNA Interference / Q000187:drug effects; D017386:Sequence Homology, Amino Acid; D013940:Thymidylate Synthase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil