Document Detail


Inhibition of the JNK signalling pathway enhances proteasome inhibitor-induced apoptosis of kidney cancer cells by suppression of BAG3 expression.
MedLine Citation:
PMID:  19681889     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Proteasome inhibitors represent a novel class of anti-tumour agents that have clinical efficacy against haematological and solid cancers. The anti-apoptotic protein BAG3 is a member of the Bcl-2-associated athanogene family. We have previously shown that BAG3 is up-regulated after exposure to proteasome inhibitors and that inhibition of BAG3 sensitized cells to apoptosis induced by proteasome inhibition. However, the mechanisms by which proteasome inhibition induced BAG3 expression remained unclear and the present experiments were designed to elucidate these mechanisms.
EXPERIMENTAL APPROACH: Effects of the proteasome inhibitor MG132 on activation of mitogenic signalling pathways were evaluated in kidney cancer cells (A498, Caki1, Caki2), with Western blotting. Specific inhibitors against individual mitogenic signalling pathways, real-time reverse transcription-polymerase chain reaction and luciferase reporter assays were used to investigate the roles of mitogenic signalling pathways in BAG3 induction after proteasome inhibition. Cell death was evaluated using Annexin V/propidium iodide staining and subsequent FACS.
KEY RESULTS: MG132 activated several key mitogenic signalling pathways including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activities. Induction of BAG3 by MG132 was inhibited by blocking JNK, but not ERK1/2 and p38 MAPK signalling pathways. In addition, SP600125 and dominant-negative JNK1 suppressed BAG3 promoter-driven reporter gene expression. Furthermore, activation of the JNK pathway induced BAG in kidney cancer cells after treatment with MG132.
CONCLUSIONS AND IMPLICATIONS: Our results suggested that the JNK pathway was associated with the protective response against proteasome inhibition, by mediating induction of BAG3.
Authors:
Hua-Qin Wang; Bao-Qin Liu; Yan-Yan Gao; Xin Meng; Yifu Guan; Hai-Yan Zhang; Zhen-Xian Du
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-08-13
Journal Detail:
Title:  British journal of pharmacology     Volume:  158     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-10-28     Completed Date:  2010-02-12     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1405-12     Citation Subset:  IM    
Affiliation:
Department of Biochemistry & Molecular Biology, China Medical University, Shenyang, China. wanghq_doctor@hotmail.com
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / biosynthesis*
Anthracenes / pharmacology*
Apoptosis*
Cell Line, Tumor
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Flavonoids / pharmacology
Humans
Imidazoles / pharmacology
JNK Mitogen-Activated Protein Kinases / physiology*
Kidney Neoplasms
Leupeptins / pharmacology
Mitogen-Activated Protein Kinase 8 / genetics
Proteasome Inhibitors*
Pyridines / pharmacology
Signal Transduction
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Chemical
Reg. No./Substance:
0/2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 0/Adaptor Proteins, Signal Transducing; 0/Anthracenes; 0/BAG3 protein, human; 0/Flavonoids; 0/Imidazoles; 0/Leupeptins; 0/Proteasome Inhibitors; 0/Pyridines; 0/SB 203580; 0/anthra(1,9-cd)pyrazol-6(2H)-one; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinase 8; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases
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