Document Detail


Multifunctional role of Bcl-2 in malignant transformation and tumorigenesis of Cr(VI)-transformed lung cells.
MedLine Citation:
PMID:  22666341     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
B-cell lymphoma-2 (Bcl-2) is an antiapoptotic protein known to be important in the regulation of apoptosis in various cell types. However, its role in malignant transformation and tumorigenesis of human lung cells is not well understood. We previously reported that chronic exposure of human lung epithelial cells to the carcinogenic hexavalent chromium Cr(VI) caused malignant transformation and Bcl-2 upregulation; however, the role of Bcl-2 in the transformation is unclear. Using a gene silencing approach, we showed that Bcl-2 plays an important role in the malignant properties of Cr(VI)-transformed cells. Downregulation of Bcl-2 inhibited the invasive and proliferative properties of the cells as well as their colony forming and angiogenic activities, which are upregulated in the transformed cells as compared to control cells. Furthermore, animal studies showed the inhibitory effect of Bcl-2 knockdown on the tumorigenesis of Cr(VI)-transformed cells. The role of Bcl-2 in malignant transformation and tumorigenesis was confirmed by gene silencing experiments using human lung carcinoma NCI-H460 cells. These cells exhibited aggressive malignant phenotypes similar to those of Cr(VI)-transformed cells. Knockdown of Bcl-2 in the H460 cells inhibited malignant and tumorigenic properties of the cells, indicating the general role of Bcl-2 in human lung tumorigenesis. Ingenuity Pathways Analysis (IPA) revealed potential effectors of Bcl-2 in tumorigenesis regulation. Additionally, using IPA together with ectopic expression of p53, we show p53 as an upstream regulator of Bcl-2 in Cr(VI)-transformed cells. Together, our results indicate the novel and multifunctional role of Bcl-2 in malignant transformation and tumorigenesis of human lung epithelial cells chronically exposed to Cr(VI).
Authors:
Djordje Medan; Sudjit Luanpitpong; Neelam Azad; Liying Wang; Bing-Hua Jiang; Mary E Davis; John B Barnett; Lan Guo; Yon Rojanasakul
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-29
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-06-05     Completed Date:  2012-10-29     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e37045     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia, United States of America.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Cell Transformation, Neoplastic / drug effects*
Chromium / toxicity*
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockdown Techniques
Gene Silencing
Humans
Lung / pathology*
Lung Neoplasms / blood supply,  genetics,  metabolism,  pathology*
Male
Mice
Neoplasm Invasiveness
Neovascularization, Pathologic / metabolism
Proto-Oncogene Proteins c-bcl-2 / deficiency,  genetics,  metabolism*
Tumor Suppressor Protein p53 / metabolism
Grant Support
ID/Acronym/Agency:
HL076340-04S1/HL/NHLBI NIH HHS; HL095579/HL/NHLBI NIH HHS; P20-RR016477/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Proto-Oncogene Proteins c-bcl-2; 0/Tumor Suppressor Protein p53; 18540-29-9/chromium hexavalent ion; 7440-47-3/Chromium
Comments/Corrections

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