Document Detail


MMP-2 siRNA induced Fas/CD95-mediated extrinsic II apoptotic pathway in the A549 lung adenocarcinoma cell line.
MedLine Citation:
PMID:  17599056     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have previously reported that the downregulation of MMP-2 by adenovirus-mediated delivery of MMP-2 siRNA (Ad-MMP-2) reduced spheroid invasion and angiogenesis in vitro, and, metastasis and tumor growth in vivo. In this study, we investigated the mechanism of Ad-MMP-2-mediated growth inhibition in vitro and in vivo. Ad-MMP-2 infection led to the induction of apoptosis as determined by TUNEL assay, Annexin-V staining and PARP-1 cleavage in a dose-dependent manner in A549 cells. Ad-MMP-2 decreased the content of the antiapoptotic members of the Bcl-2 family proteins (Bcl-2 and Bcl-xL) and increased the content of the pro-apoptotic members of the Bcl-2 family (Bax and Bcl-xS) as determined by immunoblotting analysis. Furthermore, Ad-MMP-2-mediated apoptosis was accompanied by increase in truncated Bid, release of cytochrome c and the activation of caspase-8, -9 and -3. Immunoblot analysis showed that Ad-MMP-2 infection caused upregulation of Fas/Fas-L and FADD, and Anti-Fas-L antibody reversed Ad-MMP-2-induced apoptosis. Tissue inhibitor of metalloproteinases (TIMP)-3, an endogenous inhibitor of MMP-2, which cleaves Fas-L and activates the Fas/Fas-L inducing apoptotic pathway, was increased in Ad-MMP-2-treated cells. Adenovirus-mediated expression of MMP-2 siRNA in human lung xenografts in vivo resulted in increased immunostaining of Fas, Fas-L, cleaved Bid and TIMP-3. This is the first report, to our knowledge, showing that MMP-2 inhibition upregulates TIMP-3 levels, which in turn, promotes apoptosis in lung cancer.
Authors:
C Chetty; P Bhoopathi; S S Lakka; J S Rao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-06-25
Journal Detail:
Title:  Oncogene     Volume:  26     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-12-06     Completed Date:  2008-01-15     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  7675-83     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / enzymology*
Adenoviridae / genetics
Animals
Antigens, CD95 / analysis,  metabolism*
Apoptosis*
Caspases / metabolism
Cell Line, Tumor
Cell Proliferation
Fas Ligand Protein / analysis
Fas-Associated Death Domain Protein / metabolism
Humans
Lung Neoplasms / enzymology*
Matrix Metalloproteinase 2 / genetics
Matrix Metalloproteinase Inhibitors*
Mice
Poly(ADP-ribose) Polymerases / metabolism
Proto-Oncogene Proteins c-bcl-2 / metabolism
RNA, Small Interfering / genetics
Tissue Inhibitor of Metalloproteinase-3 / metabolism
bcl-2-Associated X Protein / metabolism
Grant Support
ID/Acronym/Agency:
CA116708/CA/NCI NIH HHS; CA75557/CA/NCI NIH HHS; CA92393/CA/NCI NIH HHS; CA95058/CA/NCI NIH HHS; NS47699/NS/NINDS NIH HHS; NS57529/NS/NINDS NIH HHS; R01 CA075557/CA/NCI NIH HHS; R01 CA075557-09/CA/NCI NIH HHS; R01 CA092393/CA/NCI NIH HHS; R01 CA092393-04/CA/NCI NIH HHS; R01 CA095058/CA/NCI NIH HHS; R01 CA095058-03/CA/NCI NIH HHS; R01 CA116708/CA/NCI NIH HHS; R01 CA116708-02/CA/NCI NIH HHS; R01 NS047699/NS/NINDS NIH HHS; R01 NS047699-03/NS/NINDS NIH HHS; R01 NS057529/NS/NINDS NIH HHS; R01 NS057529-01/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD95; 0/FADD protein, human; 0/Fas Ligand Protein; 0/Fas-Associated Death Domain Protein; 0/Matrix Metalloproteinase Inhibitors; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Small Interfering; 0/Tissue Inhibitor of Metalloproteinase-3; 0/bcl-2-Associated X Protein; EC 2.4.2.30/PARP1 protein, human; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Caspases; EC 3.4.24.24/Matrix Metalloproteinase 2
Comments/Corrections

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