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Molecular Cancer
Published in: Molecular Cancer 1/2006

Open Access 01-12-2006 | Research

Expression of the bile acid receptor FXR in Barrett's esophagus and enhancement of apoptosis by guggulsterone in vitro

Authors: Andrea De Gottardi, Jean-Marc Dumonceau, Fabien Bruttin, Alain Vonlaufen, Isabelle Morard, Laurent Spahr, Laura Rubbia-Brandt, Jean-Louis Frossard, Winand NM Dinjens, Peter S Rabinovitch, Antoine Hadengue

Published in: Molecular Cancer | Issue 1/2006

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Abstract

Background

Barrett's esophagus, a risk factor for esophageal adenocarcinoma, is associated with reflux disease. The aim of this study was to assess the expression of bile acid receptors in the esophagus (normal, esophagitis, Barrett's esophagus and adenocarcinoma) and to investigate their possible function.

Results

the expression of the bile acid receptors FXR and VDR in esophageal biopsies from patients with a normal mucosa, esophagitis, Barrett's esophagus or adenocarcinoma (n = 6 per group) and in cell lines derived from Barrett's esophagus and esophageal adenocarcinoma, was assessed by real time Q-PCR and immunohistochemistry. The effect of guggulsterone, an antagonist of bile acid receptors, on apoptosis of Barrett's esophagus-derived cells was assessed morphologically, by flow cytometry and by measuring caspase 3 activity.
The expression of FXR was increased in esophagitis, Barrett's esophagus and adenocarcinoma compared to normal mucosa by a mean of 44, 84 and 16, respectively. Immunohistochemistry showed a weak expression in normal esophagus, a strong focal reactivity in Barrett's esophagus, and was negative in adenocarcinoma. VDR expression did not significantly differ between groups. In cell cultures, the expression of FXR was high in Barrett's esophagus-derived cells and almost undetectable in adenocarcinoma-derived cells, whereas VDR expression in these cell lines was not significantly different. In vitro treatment with guggulsterone was associated with a significant increase in the percentage of apoptotic cells and of the caspase 3 activity.

Conclusion

the bile acid receptor FXR is significantly overexpressed in Barrett's esophagus compared to normal mucosa, esophagitis and esophageal adenocarcinoma. The induction of apoptosis by guggulsterone in a Barrett's esophagus-derived cell line suggests that FXR may contribute to the regulation of apoptosis.
Appendix
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Literature
1.
Sampliner RE: Practice guidelines on the diagnosis, surveillance, and therapy of Barrett's esophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol. 1998, 93 (7): 1028-1032. 10.1111/j.1572-0241.1998.00362.xCrossRefPubMed
2.
Axelrad AM, Fleischer DE: Esophageal tumors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. Edited by: Feldman M, Scharschmidt BF, Sleisenger MH. 1998, 540-554. Philadelphia , W.B. Saunders Company.
3.
Drewitz DJ, Sampliner RE, Garewal HS: The incidence of adenocarcinoma in Barrett's esophagus: a prospective study of 170 patients followed 4.8 years. Am J Gastroenterol. 1997, 92 (2): 212-215.PubMed
4.
Nehra D, Howell P, Williams CP, Pye JK, Beynon J: Toxic bile acids in gastro-oesophageal reflux disease: influence of gastric acidity. Gut. 1999, 44 (5): 598-602.PubMedCentralCrossRefPubMed
5.
Vaezi MF, Singh S, Richter JE: Role of acid and duodenogastric reflux in esophageal mucosal injury: a review of animal and human studies. Gastroenterology. 1995, 108 (6): 1897-1907. 10.1016/0016-5085(95)90156-6CrossRefPubMed
6.
Goldstein SR, Yang GY, Curtis SK, Reuhl KR, Liu BC, Mirvish SS, Newmark HL, Yang CS: Development of esophageal metaplasia and adenocarcinoma in a rat surgical model without the use of a carcinogen. Carcinogenesis. 1997, 18 (11): 2265-2270. 10.1093/carcin/18.11.2265CrossRefPubMed
7.
Nishijima K, Miwa K, Miyashita T, Kinami S, Ninomiya I, Fushida S, Fujimura T, Hattori T: Impact of the biliary diversion procedure on carcinogenesis in Barrett's esophagus surgically induced by duodenoesophageal reflux in rats. Ann Surg. 2004, 240 (1): 57-67. 10.1097/01.sla.0000130850.31178.8cPubMedCentralCrossRefPubMed
8.
van der Woude CJ, Jansen PL, Tiebosch AT, Beuving A, Homan M, Kleibeuker JH, Moshage H: Expression of apoptosis-related proteins in Barrett's metaplasia-dysplasia-carcinoma sequence: a switch to a more resistant phenotype. Hum Pathol. 2002, 33 (7): 686-692. 10.1053/hupa.2002.124908CrossRefPubMed
9.
Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B: Identification of a nuclear receptor for bile acids. Science. 1999, 284 (5418): 1362-1365. 10.1126/science.284.5418.1362CrossRefPubMed
10.
Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR, Mangelsdorf DJ: Vitamin D receptor as an intestinal bile acid sensor. Science. 2002, 296 (5571): 1313-1316. 10.1126/science.1070477CrossRefPubMed
11.
Repa JJ, Mangelsdorf DJ: The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol. 2000, 16: 459-481. 10.1146/annurev.cellbio.16.1.459CrossRefPubMed
12.
De Gottardi A, Touri F, Maurer CA, Perez A, Maurhofer O, Ventre G, Bentzen CL, Niesor EJ, Dufour JF: The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer. Dig Dis Sci. 2004, 49 (6): 982-989. 10.1023/B:DDAS.0000034558.78747.98CrossRefPubMed
13.
Shishodia S, Aggarwal BB: Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis. J Biol Chem. 2004, 279 (45): 47148-47158. 10.1074/jbc.M408093200CrossRefPubMed
14.
Nagpal S, Na S, Rathnachalam R: Noncalcemic actions of vitamin D receptor ligands. Endocr Rev. 2005, 26 (5): 662-687. 10.1210/er.2004-0002CrossRefPubMed
15.
Zhang H, LeCulyse E, Liu L, Hu M, Matoney L, Zhu W, Yan B: Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation. Arch Biochem Biophys. 1999, 368 (1): 14-22. 10.1006/abbi.1999.1307CrossRefPubMed
16.
Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, Rupar MJ, Gunyuzlu PL, Haws TF, Kassam A, Powell F, Hollis GF, Young PR, Mukherjee R, Burn TC: Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene. 2002, 290 (1-2): 35-43. 10.1016/S0378-1119(02)00557-7CrossRefPubMed
17.
Niesor EJ, Flach J, Lopes-Antoni I, Perez A, Bentzen CL: The nuclear receptors FXR and LXRalpha: potential targets for the development of drugs affecting lipid metabolism and neoplastic diseases. Curr Pharm Des. 2001, 7 (4): 231-259. 10.2174/1381612013398185CrossRefPubMed
18.
Katada N, Hinder RA, Smyrk TC, Hirabayashi N, Perdikis G, Lund RJ, Woodward T, Klingler PJ: Apoptosis is inhibited early in the dysplasia-carcinoma sequence of Barrett esophagus. Arch Surg. 1997, 132 (7): 728-733.CrossRefPubMed
19.
Dvorakova K, Payne CM, Ramsey L, Bernstein H, Holubec H, Chavarria M, Bernstein C, Sampliner RE, Riley C, Prasad A, Garewal H: Apoptosis resistance in Barrett's esophagus: ex vivo bioassay of live stressed tissues. Am J Gastroenterol. 2005, 100 (2): 424-431. 10.1111/j.1572-0241.2005.40932.xCrossRefPubMed
20.
Morales CP, Souza RF, Spechler SJ: Hallmarks of cancer progression in Barrett's oesophagus. Lancet. 2002, 360 (9345): 1587-1589. 10.1016/S0140-6736(02)11569-8CrossRefPubMed
21.
Urizar NL, Liverman AB, Dodds DT, Silva FV, Ordentlich P, Yan Y, Gonzalez FJ, Heyman RA, Mangelsdorf DJ, Moore DD: A natural product that lowers cholesterol as an antagonist ligand for FXR. Science. 2002, 296 (5573): 1703-1706. 10.1126/science.1072891CrossRefPubMed
22.
Burris TP, Montrose C, Houck KA, Osborne HE, Bocchinfuso WP, Yaden BC, Cheng CC, Zink RW, Barr RJ, Hepler CD, Krishnan V, Bullock HA, Burris LL, Galvin RJ, Bramlett K, Stayrook KR: The hypolipidemic natural product guggulsterone is a promiscuous steroid receptor ligand. Mol Pharmacol. 2005, 67 (3): 948-954. 10.1124/mol.104.007054CrossRefPubMed
23.
Alberts DS, Hallum AV, Stratton-Custis M, Garcia DJ, Gleason-Guzman M, Salmon SE, Santabarbara P, Niesor EJ, Floret S, Bentzen CL: Phase I pharmacokinetic trial and correlative in vitro phase II tumor kinetic study of Apomine (SR-45023A), a novel oral biphosphonate anticancer drug. Clin Cancer Res. 2001, 7 (5): 1246-1250.PubMed
24.
Bishop-Bailey D, Walsh DT, Warner TD: Expression and activation of the farnesoid X receptor in the vasculature. Proc Natl Acad Sci U S A. 2004, 101 (10): 3668-3673. 10.1073/pnas.0400046101PubMedCentralCrossRefPubMed
25.
Pera M, Trastek VF, Carpenter HA, Fernandez PL, Cardesa A, Mohr U, Pairolero PC: Influence of pancreatic and biliary reflux on the development of esophageal carcinoma. Ann Thorac Surg. 1993, 55 (6): 1386-92; discussion 1392-3.CrossRefPubMed
26.
Lagergren J, Bergstrom R, Lindgren A, Nyren O: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999, 340 (11): 825-831. 10.1056/NEJM199903183401101CrossRefPubMed
27.
Palanca-Wessels MC, Klingelhutz A, Reid BJ, Norwood TH, Opheim KE, Paulson TG, Feng Z, Rabinovitch PS: Extended lifespan of Barrett's esophagus epithelium transduced with the human telomerase catalytic subunit: a useful in vitro model. Carcinogenesis. 2003, 24 (7): 1183-1190. 10.1093/carcin/bgg076CrossRefPubMed
28.
de Both NJ, Wijnhoven BP, Sleddens HF, Tilanus HW, Dinjens WN: Establishment of cell lines from adenocarcinomas of the esophagus and gastric cardia growing in vivo and in vitro. Virchows Arch. 2001, 438 (5): 451-456. 10.1007/s004280000358CrossRefPubMed
29.
Philpott NJ, Turner AJ, Scopes J, Westby M, Marsh JC, Gordon-Smith EC, Dalgleish AG, Gibson FM: The use of 7-amino actinomycin D in identifying apoptosis: simplicity of use and broad spectrum of application compared with other techniques. Blood. 1996, 87 (6): 2244-2251.PubMed
Metadata
Title
Expression of the bile acid receptor FXR in Barrett's esophagus and enhancement of apoptosis by guggulsterone in vitro
Authors
Andrea De Gottardi
Jean-Marc Dumonceau
Fabien Bruttin
Alain Vonlaufen
Isabelle Morard
Laurent Spahr
Laura Rubbia-Brandt
Jean-Louis Frossard
Winand NM Dinjens
Peter S Rabinovitch
Antoine Hadengue
Publication date
01-12-2006
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2006
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-5-48

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