Back to Search
Start Over
Bile acid reflux contributes to development of esophageal adenocarcinoma via activation of phosphatidylinositol-specific phospholipase Cgamma2 and NADPH oxidase NOX5-S.
- Source :
-
Cancer research [Cancer Res] 2010 Feb 01; Vol. 70 (3), pp. 1247-55. Date of Electronic Publication: 2010 Jan 19. - Publication Year :
- 2010
-
Abstract
- Gastroesophageal reflux disease complicated by Barrett's esophagus (BE) is a major risk factor for esophageal adenocarcinoma (EA). However, the mechanisms of the progression from BE to EA are not fully understood. Besides acid reflux, bile acid reflux may also play an important role in the progression from BE to EA. In this study, we examined the role of phosphatidylinositol-specific phospholipase C (PI-PLC) and a novel NADPH oxidase NOX5-S in bile acid-induced increase in cell proliferation. We found that taurodeoxycholic acid (TDCA) significantly increased NOX5-S expression, hydrogen peroxide (H(2)O(2)) production, and cell proliferation in EA cells. The TDCA-induced increase in cell proliferation was significantly reduced by U73122, an inhibitor of PI-PLC. PI-PLCbeta1, PI-PLCbeta3, PI-PLCbeta4, PI-PLCgamma1, and PI-PLCgamma2, but not PI-PLCbeta2 and PI-PLCdelta1, were detectable in FLO cells by Western blot analysis. Knockdown of PI-PLCgamma2 or extracellular signal-regulated kinase (ERK) 2 mitogen-activated protein (MAP) kinase with small interfering RNAs (siRNA) significantly decreased TDCA-induced NOX5-S expression, H(2)O(2) production, and cell proliferation. In contrast, knockdown of PI-PLCbeta1, PI-PLCbeta3, PI-PLCbeta4, PI-PLCgamma1, or ERK1 MAP kinase had no significant effect. TDCA significantly increased ERK2 phosphorylation, an increase that was reduced by U73122 or PI-PLCgamma2 siRNA. We conclude that TDCA-induced increase in NOX5-S expression and cell proliferation may depend on sequential activation of PI-PLCgamma2 and ERK2 MAP kinase in EA cells. It is possible that bile acid reflux present in patients with BE may increase reactive oxygen species production and cell proliferation via activation of PI-PLCgamma2, ERK2 MAP kinase, and NADPH oxidase NOX5-S, thereby contributing to the development of EA.
- Subjects :
- Adenocarcinoma genetics
Adenocarcinoma metabolism
Adenocarcinoma pathology
Bile Reflux metabolism
Bile Reflux pathology
Blotting, Western
Cell Line, Tumor
Cell Proliferation
Cholagogues and Choleretics pharmacology
Enzyme Activation drug effects
Esophageal Neoplasms genetics
Esophageal Neoplasms metabolism
Esophageal Neoplasms pathology
Estrenes pharmacology
Gene Expression Regulation, Enzymologic drug effects
Gene Expression Regulation, Neoplastic drug effects
Humans
Hydrogen Peroxide metabolism
Isoenzymes genetics
Isoenzymes metabolism
Membrane Proteins genetics
Mitogen-Activated Protein Kinase 1 genetics
Mitogen-Activated Protein Kinase 1 metabolism
NADPH Oxidase 5
NADPH Oxidases genetics
Phosphodiesterase Inhibitors pharmacology
Phospholipase C gamma antagonists & inhibitors
Phospholipase C gamma genetics
Pyrrolidinones pharmacology
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Taurodeoxycholic Acid pharmacology
Bile Acids and Salts metabolism
Membrane Proteins metabolism
NADPH Oxidases metabolism
Phospholipase C gamma metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 70
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 20086178
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-09-2774