Acid- and bile-induced PGE2release and hyperproliferation in Barrett's esophagus are COX-2 and PKC-ε dependent

2002 ◽  
Vol 283 (2) ◽  
pp. G327-G334 ◽  
Author(s):  
Baljeet S. Kaur ◽  
George Triadafilopoulos
Keyword(s):  
Bile Salt ◽  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Bile Salts ◽  
Bile Reflux ◽  
Salt Mixture ◽  
Dramatic Decrease ◽  
Pkc Inhibitor ◽  
Kinase C ◽  
Cox 2

Barrett's esophagus (BE) results from acid and bile reflux and predisposes to cancer. To further understand the mechanisms of acid- and bile-induced hyperproliferation in BE, we investigated the release of PGE2in response to acid or bile salt exposure. Biopsies of esophagus, BE, and duodenum were exposed to a bile salt mixture as a 1-h pulse and compared with exposure to pH 7.4 for up to 24 h, and PGE2release, cyclooxygenase-2 (COX-2), and protein kinase C (PKC) expression were compared. Similar experiments were also performed with acidified media (pH 3.5) alone, in the presence or absence of bisindolylmaleimide (BIM), a selective PKC inhibitor, and NS-398, a COX-2 inhibitor. One-hour pulses of bile salts or acid significantly enhanced proliferation, COX-2 expression, and PGE2release in BE. In contrast, the combination pulse of acid and bile salts had no such effect. Treatment with either BIM or NS-398 led to a dramatic decrease in PGE2release in BE explants and a suppression of proliferation. The acid- or bile salt-mediated hyperproliferation is related to PGE2release. Acid- and bile salt-induced induction of COX-2 and PKC may explain, at least in part, the tumor-promoting effects of acid and bile in BE.

Bile salts induce or blunt cell proliferation in Barrett's esophagus in an acid-dependent fashion

2000 ◽  
Vol 278 (6) ◽  
pp. G1000-G1009 ◽  
Author(s):  
Baljeet S. Kaur ◽  
Rodica Ouatu-Lascar ◽  
M. Bishr Omary ◽  
George Triadafilopoulos
Keyword(s):  
Cell Proliferation ◽  
Bile Salt ◽  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Bile Salts ◽  
Bile Reflux ◽  
Salt Mixture ◽  
Complete Obliteration ◽  
Protein Kinase C Inhibitor ◽  
Incorporation Assay

Barrett's esophagus (BE) results from acid and bile reflux and predisposes to cancer. We investigated the effect of bile salts, with or without acid, on cell proliferation in BE and assessed mechanism(s) involved. To mimic physiological conditions, biopsies of esophagus, BE, and duodenum were exposed to a bile salt mixture, either continuously or as a 1-h pulse, and were compared with control media without bile salts (pH 7.4) for ≤24 h. Similar experiments were also performed with acidified media (pH 3.5) combined with the bile salt mixture as a 1-h pulse. Cell proliferation was assessed by a [3H]thymidine incorporation assay with or without bisindolylmaleimide (BIM), a selective protein kinase C inhibitor. Bile salt pulses enhanced cell proliferation in BE without affecting cell proliferation in esophageal or duodenal epithelia. In the presence of BIM, there was complete obliteration of the bile salt-induced BE hyperproliferation. In contrast, 1-h pulses of bile salts in combination with acid significantly inhibited proliferation in BE but had no effect on esophagus or duodenum. We conclude that in BE explants, brief exposure to bile salts, in the absence of acid, increases proliferation, whereas exposure to a combination of bile salts and acid together inhibits proliferation.

Contribution of stromal and epithelial cells to cyclooxygenase-2 (COX-2) activity in Barrett's esophagus

2001 ◽  
Vol 120 (5) ◽  
pp. A78-A79
Author(s):  
N BUTTAR ◽  
K WANG ◽  
M ANDERSON ◽  
L LUTZKE ◽  
K KRISHNADATH
Keyword(s):  
Epithelial Cells ◽  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Cyclooxygenase 2 ◽  
Cox 2

Bile salt exposure increases proliferation through p38 and ERK MAPK pathways in a non-neoplastic Barrett’s cell line

2006 ◽  
Vol 290 (2) ◽  
pp. G335-G342 ◽  
Author(s):  
Kshama Jaiswal ◽  
Christie Lopez-Guzman ◽  
Rhonda F. Souza ◽  
Stuart J. Spechler ◽  
George A. Sarosi
Keyword(s):  
Bile Salt ◽  
Cell Line ◽  
P38 Mapk ◽  
Bile Salts ◽  
Bile Reflux ◽  
Cell Number ◽  
Brdu Incorporation ◽  
Neoplastic Progression ◽  
Mapk Pathways ◽  
Cell Counts

Bile reflux has been implicated in the neoplastic progression of Barrett’s esophagus (BE). Bile salts increase proliferation in a Barrett’s-associated adenocarcinoma cell line (SEG-1 cells) by activating ERK and p38 MAPK pathways. However, it is not clear that these findings in cancer cells are applicable to non-neoplastic cells of benign BE. We examined the effect of bile salts on three human cell lines: normal esophageal squamous (NES) cells, non-neoplastic Barrett’s cells (BAR cells), and SEG-1 cells. We hypothesized that bile salt exposure activates proproliferative and antiapoptotic pathways to promote increased growth in BE. NES, BAR, and SEG-1 cells were exposed to glycochenodeoxycholic acid (GCDA) at a neutral pH for 5 min. Proliferation was measured by Coulter counter cell counts and a 5-bromo-2′-deoxyuridine (BrdU) incorporation assay. GCDA-induced MAPK activation was examined by Western blot analysis for phosphorylated ERK and p38. Apoptosis was measured by TdT-mediated dUTP nick-end labeling and annexin V staining after GCDA and UV-B exposure. Statistical significance was determined by ANOVA. NES cells exposed to 5 min of GCDA did not increase cell number. In BAR cells, GCDA exposure increased cell number by 31%, increased phosphorylated p38 and ERK levels by two- to three-fold, increased BrdU incorporation by 30%, and decreased UV-induced apoptosis by 15–20%. In conclusion, in a non-neoplastic Barrett’s cell line, GCDA exposure induces proliferation by activation of both ERK and p38 MAPK pathways. These findings suggest a potential mechanism whereby bile reflux may facilitate the neoplastic progression of BE.

scholarly journals In Barrett’s epithelial cells, weakly acidic bile salt solutions cause oxidative DNA damage with response and repair mediated by p38

2020 ◽  
Vol 318 (3) ◽  
pp. G464-G478
Author(s):  
Xiaofang Huo ◽  
Kerry B. Dunbar ◽  
Xi Zhang ◽  
Qiuyang Zhang ◽  
Stuart Jon Spechler ◽  
...  
Keyword(s):  
Dna Damage ◽  
Bile Salt ◽  
Barrett’S Esophagus ◽  
Esophageal Adenocarcinoma ◽  
Dna Damage Response ◽  
Barrett's Esophagus ◽  
Oxidative Dna Damage ◽  
Damage Response ◽  
Barrett's Metaplasia ◽  
Barrett’S Metaplasia

The frequency of esophageal adenocarcinoma is rising despite widespread use of proton pump inhibitors (PPIs), which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett’s esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett’s cells. Because p53 is inactivated frequently in Barrett’s esophagus and p38 can assume p53 functions, we explored p38’s role in DNA damage response and repair. We exposed Barrett’s cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38 dependent. We also measured phospho-p38 in biopsies of Barrett’s metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced bromodeoxyuridine incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease I (Ref-1/APE1). Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All of these effects were observed in p53-intact and p53-deficient Barrett’s cells. In patients, esophageal DCA perfusion significantly increased phospho-p38 in Barrett’s metaplasia. WABM exposure generates ROS, causing oxidative DNA damage in Barrett’s cells, a mechanism possibly underlying the rising frequency of esophageal adenocarcinoma despite PPI usage. p38 plays a central role in oxidative DNA damage response and Ref-1/APE1-associated BER, suggesting potential chemopreventive roles for agents like UDCA that increase p38 activity in Barrett’s esophagus. NEW & NOTEWORTHY We found that weakly acidic bile salt solutions, with compositions similar to the refluxed gastric juice of gastroesophageal reflux disease patients on proton pump inhibitors, cause oxidative DNA damage in Barrett’s metaplasia that could contribute to the development of esophageal adenocarcinoma. We also have elucidated a critical role for p38 in Barrett’s metaplasia in its response to and repair of oxidative DNA damage, suggesting a potential chemopreventive role for agents like ursodeoxycholic acid that increase p38 activity in Barrett’s esophagus.

Cyclooxygenase 2 expression in Barrett's esophagus and adenocarcinoma: Ex vivo induction by bile salts and acid exposure

2000 ◽  
Vol 118 (3) ◽  
pp. 487-496 ◽  
Author(s):  
Vivian N. Shirvani ◽  
Rodica Ouatu-Lascar ◽  
Baljeet S. Kaur ◽  
M.Bishr Omary ◽  
George Triadafilopoulos
Keyword(s):  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Bile Salts ◽  
Ex Vivo ◽  
Cyclooxygenase 2 ◽  
Acid Exposure

Cyclooxygenase-2 (COX-2) mediated anti-apoptosis may occur via Bcl-2 in the progression of Barrett's esophagus to adenocarcinoma

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 9529-9529 ◽  
Author(s):  
D. Shimizu ◽  
J. H. Peters ◽  
D. Vallboehmer ◽  
H. Kuramochi ◽  
K. Uchida ◽  
...  
Keyword(s):  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Cyclooxygenase 2 ◽  
Cox 2

Cyclooxygenase-2 (COX-2) mediated anti-apoptosis may occur via Bcl-2 in the progression of Barrett's esophagus to adenocarcinoma

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 9529-9529
Author(s):  
D. Shimizu ◽  
J. H. Peters ◽  
D. Vallboehmer ◽  
H. Kuramochi ◽  
K. Uchida ◽  
...  
Keyword(s):  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Cyclooxygenase 2 ◽  
Cox 2

Expression of cyclo-oxygenase 2 (COX-2) in Barrett's esophagus, dysplasia and adenocarcinoma

2000 ◽  
Vol 118 (4) ◽  
pp. A685 ◽  
Author(s):  
Clive D. Morris ◽  
Graham Bigley ◽  
Gordon R. Armstrong ◽  
Stephen E. Attwood
Keyword(s):  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Cox 2
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