PMID- 23619566
OWN - NLM
STAT- MEDLINE
DCOM- 20140117
LR  - 20130522
IS  - 1791-2431 (Electronic)
IS  - 1021-335X (Linking)
VI  - 30
IP  - 1
DP  - 2013 Jul
TI  - NK4 regulates 5-fluorouracil sensitivity in cholangiocarcinoma cells by 
      modulating the intrinsic apoptosis pathway.
PG  - 448-54
LID - 10.3892/or.2013.2427 [doi]
AB  - The aim of the present study was to investigate the role of NK4, an antagonist 
      for hepatocyte growth factor (HGF) and the Met receptor, in regulating the 
      response of cholangiocarcinoma (CCA) cells to 5-fluorouracil (5-FU). We 
      established the CCA cell line, HuCC-T1, to produce abundant NK4 (Hu-NK4). Cell 
      proliferation, cell cycle distribution, apoptosis, 5-FU metabolism and 
      intracellular signaling were examined. There were no significant differences in 
      the mRNA levels of thymidylate synthase, thymidine phosphorylase and 
      dihydropyrimidine dehydrogenase between the mock-transfected control Hu-Em cells 
      and Hu-NK4 cells, suggesting that NK4 expression does not alter 5-FU metabolism. 
      Moreover, cell cycle analysis showed that 5-FU treatment caused a decrease in the 
      proportion of cells in the G2/M phase while NK4 gene expression had little effect 
      on the cell cycle distribution. However, 5-FU-induced apoptosis was significantly 
      increased in the Hu-NK4 cells when compared to that in the Hu-Em cells. Further 
      investigation revealed that NK4 gene expression enhanced 5-FU-induced caspase-3 
      and caspase-9 activation, and that the apoptosis of cells was associated with 
      modulation of expression of the Bcl-2 family members. Furthermore, western blot 
      analysis revealed that both NK4 and 5-FU were inhibitors for HGF-induced 
      phosphorylation of Met, but they may be independent factors. Collectively, these 
      results suggest that following 5-FU treatment in CCA cell lines, NK4 was involved 
      in apoptosis induction through the intrinsic mitochondrial pathway. This 
      indicates that NK4 may be an important mediator of 5-FU-induced cell death. 
      Moreover, downregulation of NK4 in response to 5-FU may represent an intrinsic 
      mechanism of resistance to this anticancer drug.
FAU - Ge, Xianxiu
AU  - Ge X
AD  - Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, 
      Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 
      210011, P.R. China.
FAU - Wang, Youli
AU  - Wang Y
FAU - Li, Quanpeng
AU  - Li Q
FAU - Yu, Hong
AU  - Yu H
FAU - Ji, Guozhong
AU  - Ji G
FAU - Miao, Lin
AU  - Miao L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130425
PL  - Greece
TA  - Oncol Rep
JT  - Oncology reports
JID - 9422756
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (HGF protein, human)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (RNA, Messenger)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 1.3.1.2 (Dihydrouracil Dehydrogenase (NADP))
RN  - EC 2.1.1.45 (Thymidylate Synthase)
RN  - EC 2.4.2.4 (Thymidine Phosphorylase)
RN  - EC 2.7.10.1 (MET protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 9)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Antimetabolites, Antineoplastic/*pharmacology
MH  - Apoptosis
MH  - Bile Duct Neoplasms/*metabolism
MH  - Bile Ducts, Intrahepatic/metabolism
MH  - Caspase 3/metabolism
MH  - Caspase 9/metabolism
MH  - Cell Cycle
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Cholangiocarcinoma/*metabolism
MH  - Dihydrouracil Dehydrogenase (NADP)/genetics
MH  - Drug Resistance, Neoplasm
MH  - Enzyme Activation
MH  - Fluorouracil/metabolism/*pharmacology
MH  - Hepatocyte Growth Factor/*metabolism
MH  - Humans
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-bcl-2/biosynthesis
MH  - Proto-Oncogene Proteins c-met/metabolism
MH  - RNA, Messenger/biosynthesis
MH  - Thymidine Phosphorylase/genetics
MH  - Thymidylate Synthase/genetics
EDAT- 2013/04/27 06:00
MHDA- 2014/01/18 06:00
CRDT- 2013/04/27 06:00
PHST- 2013/01/31 00:00 [received]
PHST- 2013/03/04 00:00 [accepted]
PHST- 2013/04/27 06:00 [entrez]
PHST- 2013/04/27 06:00 [pubmed]
PHST- 2014/01/18 06:00 [medline]
AID - 10.3892/or.2013.2427 [doi]
PST - ppublish
SO  - Oncol Rep. 2013 Jul;30(1):448-54. doi: 10.3892/or.2013.2427. Epub 2013 Apr 25.