Document Detail

Regulation of pancreatic cancer growth by superoxide.
MedLine Citation:
PMID:  22392697     Owner:  NLM     Status:  MEDLINE    
K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Expression of K-ras oncogene in an immortalized human pancreatic ductal epithelial cell line, originally derived from normal pancreas (H6c7), induced the formation of carcinoma in mice. We hypothesized that K-ras oncogene correlates with increased non-mitochondrial-generated superoxide (O 2.-), which could be involved in regulating cell growth contributing to tumor progression. In the H6c7 cell line and its derivatives, H6c7er-Kras+ (H6c7 cells expressing K-ras oncogene), and H6c7eR-KrasT (tumorigenic H6c7 cells expressing K-ras oncogene), there was an increase in hydroethidine fluorescence in cell lines that express K-ras. Western blots and activity assays for the antioxidant enzymes that detoxify O 2.- were similar in these cell lines suggesting that the increase in hydroethidine fluorescence was not due to decreased antioxidant capacity. To determine a possible non-mitochondrial source of the increased levels of O 2.-, Western analysis demonstrated the absence of NADPH oxidase-2 (NOX2) in H6c7 cells but present in the H6c7 cell lines expressing K-ras and other pancreatic cancer cell lines. Inhibition of NOX2 decreased hydroethidine fluorescence and clonogenic survival. Furthermore, in the cell lines with the K-ras oncogene, overexpression of superoxide dismutases that detoxify non-mitochondrial sources of O 2.-, and treatment with the small molecule O 2.- scavenger Tempol, also decreased hydroethidine fluorescence, inhibited clonogenic survival and inhibited growth of tumor xenografts. Thus, O 2.- produced by NOX2 in pancreatic cancer cells with K-ras, may regulate pancreatic cancer cell growth.
Juan Du; Elke S Nelson; Andrean L Simons; Kristen E Olney; Justin C Moser; Hannah E Schrock; Brett A Wagner; Garry R Buettner; Brian J Smith; Melissa L T Teoh; Ming-Sound Tsao; Joseph J Cullen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-03-05
Journal Detail:
Title:  Molecular carcinogenesis     Volume:  52     ISSN:  1098-2744     ISO Abbreviation:  Mol. Carcinog.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-19     Completed Date:  2013-08-20     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  8811105     Medline TA:  Mol Carcinog     Country:  United States    
Other Details:
Languages:  eng     Pagination:  555-67     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
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MeSH Terms
Blotting, Western
Cell Proliferation*
Cyclic N-Oxides
Cytosol / enzymology
Extracellular Space / enzymology
Membrane Glycoproteins / antagonists & inhibitors,  genetics,  metabolism
Mice, Nude
Mitochondria / enzymology
NADPH Oxidase / antagonists & inhibitors,  genetics,  metabolism
Pancreatic Neoplasms / metabolism,  pathology*
Phenanthridines / metabolism
Proto-Oncogene Proteins / genetics,  metabolism*
RNA, Small Interfering / genetics
Spin Labels
Superoxide Dismutase / antagonists & inhibitors,  genetics,  metabolism*
Superoxides / metabolism*
Tumor Cells, Cultured
Tumor Stem Cell Assay
ras Proteins / genetics,  metabolism*
Grant Support
CA115438/CA/NCI NIH HHS; CA137230/CA/NCI NIH HHS; P30 ES005605/ES/NIEHS NIH HHS; R01 CA169046/CA/NCI NIH HHS; R21 CA137230/CA/NCI NIH HHS; R21 CA137230-01A1/CA/NCI NIH HHS
Reg. No./Substance:
0/CYBB protein, human; 0/Cyclic N-Oxides; 0/KRAS protein, human; 0/Membrane Glycoproteins; 0/Phenanthridines; 0/Proto-Oncogene Proteins; 0/RNA, Small Interfering; 0/Spin Labels; 11062-77-4/Superoxides; 2226-96-2/tempol; 38483-26-0/hydroethidine; EC Dismutase; EC Oxidase; EC Proteins

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