Document Detail


DCK is frequently inactivated in acquired gemcitabine-resistant human cancer cells.
MedLine Citation:
PMID:  22490663     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Although gemcitabine is the most effective chemotherapeutic agent against pancreatic cancer, a growing concern is that a substantial number of patients acquire gemcitabine chemoresistance. To elucidate the mechanisms of acquisition of gemcitabine resistance, we developed gemcitabine-resistant cell lines from six human cancer cell lines; three pancreatic, one gastric, one colon, and one bile duct cancer. We first analyzed gemcitabine uptake using three paired parental and gemcitabine resistant pancreatic cancer cell lines (PK-1 and RPK-1, PK-9 and RPK-9, PK-59 and RPK-59) and found that uptake of gemcitabine was rapid. However, no DNA damage was induced in resistant cells. We further examined the microarray-based expression profiles of the cells to identify genes associated with gemcitabine resistance and found a remarkable reduction in the expression of deoxycytidine kinase (DCK). DCK is a key enzyme that activates gemcitabine by phosphorylation. Genetic alterations and expression of DCK were studied in these paired parental and derived gemcitabine-resistant cell lines, and inactivating mutations were found only in gemcitabine-resistant cell lines. Furthermore, siRNA-mediated knockdown of DCK in the parental cell lines yielded gemcitabine resistance, and introduction of DCK into gemcitabine-resistant cell lines invariably restored gemcitabine sensitivities. Mutation analyses were expanded to three other different paired cell lines, DLD-1 and RDLD-1 (colon cancer cell line), MKN-28 and RMKN-28 (gastric cancer cell line), and TFK-1 and RTFK -1 (cholangiocarcinoma cell line). We found inactivating mutations in RDLD-1 and RTFK-1 and decreased expression of DCK in RMKN-28. These results indicate that the inactivation of DCK is one of the crucial mechanisms in acquisition of gemcitabine resistance.
Authors:
Yuriko Saiki; Yuki Yoshino; Hiroko Fujimura; Tatsuya Manabe; Yuki Kudo; Miki Shimada; Nariyasu Mano; Tomohiro Nakano; Yoonha Lee; Shinjiro Shimizu; Shinya Oba; Sho Fujiwara; Hideyuki Shimizu; Na Chen; Zhaleh Kashkouli Nezhad; Guo Jin; Shinichi Fukushige; Makoto Sunamura; Masaharu Ishida; Fuyuhiko Motoi; Shinichi Egawa; Michiaki Unno; Akira Horii
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-04-03
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  421     ISSN:  1090-2104     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-05-01     Completed Date:  2012-06-22     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  98-104     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
Affiliation:
Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites, Antineoplastic / pharmacokinetics,  pharmacology*
Cell Line, Tumor
Deoxycytidine / analogs & derivatives*,  pharmacokinetics,  pharmacology
Deoxycytidine Kinase / genetics,  metabolism*
Drug Resistance, Neoplasm*
Gene Expression
Gene Knockdown Techniques
Gene Silencing
Histones / metabolism
Humans
Pancreatic Neoplasms / enzymology*
Phosphorylation
RNA, Small Interfering / genetics
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/H2AFX protein, human; 0/Histones; 0/RNA, Small Interfering; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC 2.7.1.74/Deoxycytidine Kinase

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


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