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Microenvironment effects on promoting upregulation of matrix metalloproteinases in Bcl-2-overexpressing renal cell carcinoma as a response to doxorubicin treatment inducing the production of metastasis

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Authors
Ahn, Kwang-Sung; Bae, Eunkyung; Jeon, Seong Soo; Yoon, Sung-Soo; Lee, Young-Yuil; Choi, Han-Yong
Issue Date
2007-06-02
Publisher
Karger
Citation
Tumour Biol 2007;28:181-188
Keywords
Carcinoma, Renal Cell/drug therapy/*genetics/pathologyCaspase 3/metabolismCell Line, TumorCell Survival/drug effectsDoxorubicin/*therapeutic useEnzyme-Linked Immunosorbent AssayGene Expression Regulation, EnzymologicGene Expression Regulation, NeoplasticHumansKidney Neoplasms/drug therapy/*genetics/pathologyMatrix Metalloproteinase 2/*geneticsMatrix Metalloproteinase 9/*geneticsPlasmidsProto-Oncogene Proteins c-bcl-2/*genetics
Abstract
Dysfunction in apoptosis has been suggested to play an important role in the development of a distant metastasis. The Bcl-2 gene plays a key role in the response to chemotherapeutic agents, and its upregulation protects the cells from apoptosis by inactivating the Bax proteins through heterodimerization of Bcl-2/Bax. However, there is no direct evidence showing that the upregulation of Bcl-2 increases the antiapoptotic effects against chemotherapeutic agents and is associated with the production of a distant metastasis. In this study, the role of Bcl-2 in the production of distant metastasis was investigated by examining the activity of caspase-3 and the expression of matrix metalloproteinases (MMPs) after transfecting the Bcl-2 gene into human renal cell carcinoma cells (SN12C). In addition, the production of a distant metastasis was examined in an orthotopic animal model. In vitro, the SN12C/smb2 cells were more resistant to doxorubicin (DXR) than the untreated parental cells. The IC50 of the SN12C/smb2 was 50% higher than that of the parental cells. In addition, the caspase-3 activity of the SN12C/smb2 cells was lower than that of the parental cells after the DXR treatment. On the other hand, there was no difference in the expression of MMP-2 and MMP-9 between the SN12C and SN12C/smb2 cell lines. However, the SN12C/smb2 cells had a higher metastatic potential than the parental cells in the orthotopic animal model. Unlike the results from the in vitro analysis, the expression of MMP-2 and MMP-9 in the kidney tumors produced by the SN12C/smb2 cells was higher than in the kidney tumors produced by the SN12C/vector. These results show that the upregulation of Bcl-2 in human renal cell carcinoma cells induces drug resistance to DXR. Moreover, Bcl-2 induced the expression of MMP in tumors grown in the orthotopic sites even though no appreciable effects were observed in the in vitro condition. When the in vitro and in vivo data were combined, it appears that the Bcl-2 gene initially affects the response to DXR. The cells that survive the DXR treatment then have a chance to become metastatic by increasing the levels of MMP in an orthotopic environment.
ISSN
1010-4283 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17541305

http://hdl.handle.net/10371/21622
DOI
https://doi.org/10.1159/000103381&typ=pdf

https://doi.org/10.1159/000103381
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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