Bile acids are multifunctional modulators of the Barrett’s carcinogenesis

• Autorzy: Burnat G. , Majka J. , Konturek P.C.
• Języki publikacji: EN

Abstrakty

EN

Bile salts play an important pathogenic role in the development of Barrett adenocarcinoma (BA). However, the precise role of different bile salts in this process is still unknown. The aim of the present study was to compare the effects of two different bile salts, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) on the expression of COX-2, CDX-2 and DNA repair enzymes (MUTYH, OGG-1) in the Barrett epithelial cancer cells (OE-19). OE-19 cells were incubated with DCA or UDCA (100 µM or 300 µM at pH=7.0) over 24 h. To investigate the involvement of NFB, in separate experiments the cells were incubated with DCA in the presence of proteosome inhibitor (MG-132). Cells cycle and apoptosis were analyzed by FACS analysis. After incubation of OE-19 cells with bile salts, the expression of mRNA of COX-2, DNA repair enzymes (MUTYH, OGG-1) and caudal-related homebox transcription factor CDX-2 were measured by quantitative RT-PCR. OE-19 cell were also transfected with siRNA-RelA (p65) to asses effect of NFB inactivation on COX-2 and CDX2 expression. DCA caused a stronger reduction in cell survival of OE-19 cells than UDCA. In addition, DCA stimulated directly the translocation of NFB p65 (active form) in the nuclei of OE-19 cells. DCA caused stronger than UDCA stimulation of the COX-2 mRNA expression in these cells and this effect was significantly attenuated by the addition of inhibitor of NFB activity (proteosome inhibitor MG-132). siRNA-RelA reduced expression not only of NFB but also expression of COX-2 as well as CDX-2 mRNA. DCA caused stronger downregulation of mRNA for DNA repair enzymes MUTYH and OGG-1 than UDCA. In contrast, UDCA induced stronger CDX-2 mRNA expression than DCA in OE-19 cells. We conclude that bile salts are involved in the carcinogenesis of Barrett adenocarcinoma via inhibition of DNA repair enzymes and induction of COX-2 and this last effect is, at least partly, mediated by NFB. DCA shows carcinogenic potential due to high upregulation of COX-2, CDX-2 and downregulation of DNA repair enzymes.

Słowa kluczowe

EN

Barrett's adenocarcinoma; DNA repair; apoptosis; bile acid; bile salt; carcinogenesis; cell proliferation; cyclooxygenase-2; deoxycholic acid; epithelial cell; ursodeoxycholic acid

• Wydawca: -
• Czasopismo: Journal of Physiology and Pharmacology
• Rocznik: 2010
• Tom: 61
• Numer: 2
• Opis fizyczny: p.185-192,fig.,ref.

Twórcy

autor

Burnat G.

• Teaching Hospital of the University of Jena, 68 Rainweg Street, 07318 Saalfeld/Saale, Germany

autor

Majka J.

autor

Konturek P.C.

Bibliografia

• Konturek PC, Burnat G, Hahn EG. Inhibition of Barret’s adenocarcinoma cell growth by simvastatin: involvement of COX-2 and apoptosis-related proteins. J Physiol Pharmacol 2007; 58(Suppl 3): 141-148.
• Jankowski JA, Harrison RF, Perry I, Balkwill F, Tselepis C. Barrett’s metaplasia. Lancet 2000; 356: 2079-2085.
• Falk GW. Gastroesophageal reflux disease and Barrett’s esophagus. Endoscopy 2001; 33: 109-118.
• Flejou JF. Barrett’s oesophagus: from metaplasia to dysplasia and cancer. Gut 2005; 54(Suppl 1): 16-12.
• Menges M, Muller M, Zeitz M. Increased acid and bile reflux in Barrett’s esophagus compared to reflux esophagitis, and effect of proton pump inhibitor therapy. Am J Gastroenterol 2001; 96: 331-337.
• Fein M, Fuchs KH, Stopper H, Diem S, Herderich M. Duodenogastric reflux and foregut carcinogenesis: analysis of duodenal juice in a rodent model of cancer. Carcinogenesis 2000; 21: 2079-2084.
• Miwa K, Sahara H, Segawa M, et al. Reflux of duodenal or gastro-duodenal contents induces esophageal carcinoma in rats. Int J Cancer 1996; 67: 269-274.
• Martinez JD, Stratagoules ED, LaRue JM, et al. Different bile acids exhibit distinct biological effects: the tumor promoter deoxycholic acid induces apoptosis and the chemopreventive agent ursodeoxycholic acid inhibits cell proliferation. Nutr Cancer 1998; 31: 111-118.
• Powell AA, LaRue JM, Batta AK, Martinez JD. Bile acid hydrophobicity is correlated with induction of apoptosis and/or growth arrest in HCT116 cells. Biochem J 2001; 356: 481-486.
• Konturek PC, Kania J, Burnat G, Hahn EG. NO-releasing aspirin exerts stronger growth inhibitory effect on Barrett’s adenocarcinoma cells than traditional aspirin. J Physiol Pharmacol 2006; 57(Suppl 12): 15-24.
• Konturek PC, Nikiforuk A, Kania J, Raithel M, Hahn EG, Muhldorfer S. Activation of NFkappaB represents the central event in the neoplastic progression associated with Barrett’s esophagus: a possible link to the inflammation and overexpression of COX-2, PPARgamma and growth factors. Dig Dis Sci 2004; 49: 1075-1083.
• O’Riordan JM, Abdel-latif MM, Ravi N, et al. Proinflammatory cytokine and nuclear factor kappa-B expression along the inflammation-metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Am J Gastroenterol 2005; 100: 1257-1264.
• Gerlag DM, Ransone L, Tak PP, et al. The effect of a T cell-specific NF-kappa B inhibitor on in vitro cytokine production and collagen-induced arthritis. J Immunol 2000; 165: 1652-1658.
• Olyaee M, Sontag S, Salman W, et al. A. Mucosal reactive oxygen species production in oesophagitis and Barrett’s oesophagus. Gut 1995; 37: 168-173.
• Jimenez P, Piazuelo E, Sanchez MT, Ortego J, Soteras F, Lanas A. Free radicals and antioxidant systems in reflux esophagitis and Barrett’s esophagus. World J Gastroenterol 2005; 11: 2697-2703.
• Nakabeppu Y, Tsuchimoto D, Furuichi M, Sakumi K. The defense mechanisms in mammalian cells against oxidative damage in nucleic acids and their involvement in the suppression of mutagenesis and cell death. Free Radic Res 2004; 38: 423-429.
• Lewandowska U, Zelazowski M, Seta K, Byczewska M, Pluciennik E, Bednarek AK. WWOX, the tumor suppressor gene affected in multiple cancers. J Physiol Pharmacol 2009; 60(Suppl 1): 47-56.
• Konturek PC, Kania J, Burnat G, Hahn EG, Konturek SJ. Prostaglandins as mediators of COX-2 derived carcinogenesis in gastrointestinal tract. J Physiol Pharmacol 2005; 56(Suppl 5): 57-73.
• Mutoh H, Hakamata Y, Sato K, et al. Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice. Biochem Biophys Res Commun 2002; 294: 470-479.
• Cayrol C, Knibiehler M, Ducommun B. p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells. Oncogene 1998; 16: 311-320.
• Beck F, Chawengsaksophak K, Waring P, Playford RJ, Furness JB. Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice. Proc Natl Acad Sci USA 1999; 96: 7318-7323.
• Moons LM, Bax DA, Kuipers EJ, et al. The homeodomain protein CDX2 is an early marker of Barrett’s oesophagus. J Clin Pathol 2004; 57: 1063-1068.
• Lord RV, Brabender J, Wickramasinghe K, et al. Increased CDX2 and decreased PITX1 homeobox gene expression in Barrett’s esophagus and Barrett’s-associated adenocarcinoma. Surgery 2005; 138: 924-931.
• Mallo GV, Soubeyran P, Lissitzky JC, et al. Expression of the Cdx1 and Cdx2 homeotic genes leads to reduced malignancy in colon cancer-derived cells. J Biol Chem 1998; 273: 14030-14036.
• Phillips RW, Frierson HF Jr., Moskaluk CA. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus. Am J Surg Pathol 2003; 27: 1442-1447.
• Kazumori H, Ishihara S, Rumi MA, Kadowaki Y, Kinoshita Y. Bile acids directly augment caudal related homeobox gene Cdx2 expression in oesophageal keratinocytes in Barrett’s epithelium. Gut 2006; 55: 16-25.
• Kim S, Domon-Dell C, Wang Q, et al. PTEN and TNF-alpha regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-kappaB-dependent pathway. Gastroenterology 2002; 123: 1163-1178.
• Croog VJ, Ullman TA, Itzkowitz SH. Chemoprevention of colorectal cancer in ulcerative colitis. Int J Colorectal Dis 2003; 18: 392-400.
• Raj A, Jankowski J. Acid suppression and chemoprevention in Barrett’s oesophagus. Dig Dis 2004; 22: 171-180.
• Konturek SJ, Zayachkivska O, Havryluk XO, et al. Protective influence of melatonin against acute esophageal lesions involves prostaglandins, nitric oxide and sensory nerves. J Physiol Pharmacol 2007; 58: 361-377.
• Konturek SJ, Konturek PC, Brzozowski T, Bubenik GA. Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol 2007; 58(Suppl 6): 23-52.
• Bubenik GA. Thirty four years since the discovery of gastrointestinal melatonin. J Physiol Pharmacol 2008; 59(Suppl 2): 33-51.
• Tobin G, Giglio D, Lundgren O. Muscarinic receptor subtypes in the alimentary tract. J Physiol Pharmacol 2009; 60: 3-21.
• Thor PJ, Blaut U. Helicobacter pylori infection in pathogenesis of gastroesophageal reflex disease. J Physiol Pharmacol 2006; 57(Suppl 3): 81-90.