Document Detail

Attenuation of phosphorylation by deoxycytidine kinase is key to acquired gemcitabine resistance in a pancreatic cancer cell line: targeted proteomic and metabolomic analyses in PK9 cells.
MedLine Citation:
PMID:  22419259     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Multiple proteins are involved in activation and inactivation of 2',2'-difluorodeoxycytidine (gemcitabine, dFdC). We aimed to clarify the mechanism of dFdC resistance in a pancreatic cancer cell line by applying a combination of targeted proteomic and metabolomic analyses.
METHODS: Twenty-five enzyme and transporter proteins and 6 metabolites were quantified in sensitive and resistant pancreatic cancer cell lines, PK9 and RPK9, respectively.
RESULTS: The protein concentration of deoxycytidine kinase (dCK) in RPK9 cells was less than 0.02-fold (2 %) compared with that in PK9 cells, whereas the differences (fold) were within a factor of 3 for other proteins. Targeted metabolomic analysis revealed that phosphorylated forms of dFdC were reduced to less than 0.2 % in RPK9 cells. The extracellular concentration of 2',2'-difluorodeoxyuridine (dFdU), an inactive metabolite of dFdC, reached the same level as the initial dFdC concentration in RPK9 cells. However, tetrahydrouridine treatment did not increase phosphorylated forms of dFdC and did not reverse dFdC resistance in RPK9 cells, though this treatment inhibits production of dFdU.
CONCLUSIONS: Combining targeted proteomics and metabolomics suggests that acquisition of resistance in RPK9 cells is due to attenuation of dFdC phosphorylation via suppression of dCK.
Ken Ohmine; Kei Kawaguchi; Sumio Ohtsuki; Fuyuhiko Motoi; Shinichi Egawa; Michiaki Unno; Tetsuya Terasaki
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-15
Journal Detail:
Title:  Pharmaceutical research     Volume:  29     ISSN:  1573-904X     ISO Abbreviation:  Pharm. Res.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-07     Completed Date:  2012-10-01     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2006-16     Citation Subset:  IM    
Division of Membrane Transport and Drug Targeting Department of Biochemical Pharmacology and Therapeutics Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan.
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MeSH Terms
Antimetabolites, Antineoplastic / pharmacology*
Cell Line, Tumor
Deoxycytidine / analogs & derivatives*,  pharmacology
Deoxycytidine Kinase / genetics,  metabolism*
Drug Resistance, Neoplasm*
Floxuridine / analogs & derivatives*,  metabolism
Gene Expression Regulation, Neoplastic
Pancreas / drug effects,  enzymology,  metabolism
Pancreatic Neoplasms / drug therapy*,  enzymology,  genetics
Reg. No./Substance:
0/2',2'-difluoro-2'-deoxyuridine; 0/Antimetabolites, Antineoplastic; 50-91-9/Floxuridine; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC Kinase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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