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
Related Documents :
9459209 - Influence of hyaluronic acid or phorbol 12-myristate 13-acetate on the migration capaci...
22285729 - Mir-181a sensitizes a multidrug-resistant leukemia cell line k562/a02 to daunorubicin b...
22484209 - Inhibition of p-glycoprotein functionality by vandetanib may reverse cancer cell resist...
10545749 - Characterization of subclonal cell lines showing high motility derived from an undiffer...
19759399 - Gm3 synthase overexpression results in reduced cell motility and in caveolin-1 upregula...
8842809 - Pc12 cell aggregation and neurite growth in gels of collagen, laminin and fibronectin.
10447889 - Ph-dependent secretion of sseb, a product of the spi-2 type iii secretion system of sal...
23358649 - Effects of waterlogging on amyloplasts and programmed cell death in endosperm cells of ...
18336209 - High throughput screening of gene functions in mammalian cells using reversely transfec...
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.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
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

Previous Document:  Comparison of Open-Flow Microperfusion and Microdialysis Methodologies When Sampling Topically Appli...
Next Document:  Keratin 8 variants are associated with cryptogenic hepatitis.