Advertisement

Digestive Diseases and Sciences

, Volume 59, Issue 10, pp 2367–2380 | Cite as

Differential Regulation of EGFR–MAPK Signaling by Deoxycholic Acid (DCA) and Ursodeoxycholic Acid (UDCA) in Colon Cancer

  • Sara M. Centuori
  • Jesse D. Martinez
Review

Abstract

A high-fat diet coincides with increased levels of bile acids. This increase in bile acids, particularly deoxycholic acid (DCA), has been strongly associated with the development of colon cancer. Conversely, ursodeoxycholic acid (UDCA) may have chemopreventive properties. Although structurally similar, DCA and UDCA present different biological and pathological effects in colon cancer progression. The differential regulation of cancer by these two bile acids is not yet fully understood. However, one possible explanation for their diverging effects is their ability to differentially regulate signaling pathways involved in the multistep progression of colon cancer, such as the epidermal growth factor receptor (EGFR)–mitogen-activated protein kinase (MAPK) pathway. This review will examine the biological effects of DCA and UDCA on colon cancer development, as well as the diverging effects of these bile acids on the oncogenic signaling pathways that play a role in colon cancer development, with a particular emphasis on bile acid regulation of the EGFR–MAPK pathway.

Keywords

Bile salts Colon cancer prevention Colon cancer progression Epidermal growth factor receptor Mitogen-activated protein kinase Mitogenic signaling 

Abbreviations

15-PGDH

15-Hydroxyprostaglandin dehydrogenase

AKT

Protein kinase B

AOM

Azoxymethane

AP-1

Activator protein 1

AR

Amphiregulin

ATF-2

Activating transcription factor 2

BRE

Brain and reproductive organ-expressed protein

CA

Cholic acid

CCK

Cholecystokinin

CDCA

Chenodeoxycholic acid

CDK2

Cyclin-dependent kinase 2

COX-2

Cyclooxygenase-2

CYP7a

Cholesterol 7 alpha-hydroxylase

DSH

Disheveled

EGFR

Epidermal growth factor receptor

ELK-1

E twenty six-like transcription factor 1

ERK1/2

Extracellular signal-regulated kinases 1 and 2

FXR-α

Farnesoid X receptor-alpha

GCDC

Glycochenodeoxycholate

GUDCA

Glycoursodeoxycholate

HDAC6

Histone deacetylase 6

HIF-1α

Hypoxia-inducible factor 1 alpha

IAP

Intestinal alkaline phosphatase

IκBα

Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha

IL-8

Interleukin 8

Irs-1

Insulin receptor substrate 1

JNK

c-Jun N-terminal kinase

LCA

Lithocholic acid

MAPK

Mitogen-activated protein kinase

MDM2

Murine double minute 2

MMP-9

Matrix metallopeptidase 9

MNNG

N-Methyl-N′-nitro-N-nitrosoguanidine

MUC2

Mucin 2

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

Nur77

Nuclear receptor subfamily 4 group A member 1

PARP

Poly (ADP-ribose) polymerase

PGE2

Prostaglandin E2

PI3K

Phosphatidylinositol 3-kinase

PKC

Protein kinase C

PLA2

Phospholipase A2

PXR

Pregnane X receptor

ROS

Reactive oxygen species

TCA

Taurocholic acid

TCDC

Taurochenodeoxycholate

TDCA

Taurodeoxycholic acid

TGF-α

Transforming growth factor alpha

TGR5

G Protein-coupled receptor

TUDCA

Tauroursodeoxycholate

uPA

Urokinase-type plasminogen activator

uPAR

Urokinase-type plasminogen activator receptor

VDR

Vitamin D receptor

VEGF

Vascular endothelial growth factor

Notes

Acknowledgments

We are thankful to Cecil J. Gomes, BS, who assisted in the editing of this manuscript and also to Josh Brownlee, BS, for assistance with production of 3-dimensional figures. This work was supported by the RO1 CA129688 and the minority supplement CA129688 S1 awarded by the National Institute of Health, to Jesse D. Martinez.

Conflict of interest

None.

References

  1. 1.
    Enhsen A, Kramer W, Wess GN. Bile acids in drug discovery. Drug Discovery Today. 1998;3:409–418.CrossRefGoogle Scholar
  2. 2.
    Hismiogullari AA, Bozdayi AM, Rahman K. Biliary lipid secretion. Turk J Gastroenterol. 2007;18:65–70.PubMedGoogle Scholar
  3. 3.
    Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. J Lipid Res. 2009;50:1509–1520.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Fukiya S, Arata M, Kawashima H, et al. Conversion of cholic acid and chenodeoxycholic acid into their 7-oxo derivatives by bacteroides intestinalis am-1 isolated from human feces. FEMS Microbiol Lett. 2009;293:263–270.PubMedCrossRefGoogle Scholar
  5. 5.
    Odermatt A, Da Cunha T, Penno CA, et al. Hepatic reduction of the secondary bile acid 7-oxolithocholic acid is mediated by 11 beta-hydroxysteroid dehydrogenase 1. Biochem J. 2011;436:621–629.PubMedCrossRefGoogle Scholar
  6. 6.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Jean-Louis S, Akare S, Ali MA, Mash EA Jr, Meuillet E, Martinez JD. Deoxycholic acid induces intracellular signaling through membrane perturbations. J Biol Chem. 2006;281:14948–14960.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    Ikegami T, Matsuzaki Y, Shoda J, Kano M, Hirabayashi N, Tanaka N. The chemopreventive role of ursodeoxycholic acid in azoxymethane-treated rats: suppressive effects on enhanced group ii phospholipase a2 expression in colonic tissue. Cancer Lett. 1998;134:129–139.PubMedCrossRefGoogle Scholar
  10. 10.
    Araki Y, Andoh A, Bamba H, et al. The cytotoxicity of hydrophobic bile acids is ameliorated by more hydrophilic bile acids in intestinal cell lines iec-6 and caco-2. Oncol Rep. 2003;10:1931–1936.PubMedGoogle Scholar
  11. 11.
    Cook JW, Kennaway EL, Kennaway NM. Production of tumours in mice by deoxycholic acid. Nature. 1940;145:627.CrossRefGoogle Scholar
  12. 12.
    Narisawa T, Magadia NE, Weisburger JH, Wynder EL. Promoting effect of bile acids on colon carcinogenesis after intrarectal instillation of n-methyl-n’-nitro-n-nitrosoguanidine in rats. J Natl Cancer Inst. 1974;53:1093–1097.PubMedGoogle Scholar
  13. 13.
    Reddy BS, Watanabe K, Weisburger JH, Wynder EL. Promoting effect of bile acids in colon carcinogenesis in germ-free and conventional f344 rats. Cancer Res. 1977;37:3238–3242.PubMedGoogle Scholar
  14. 14.
    Reddy BS, Narasawa T, Weisburger JH, Wynder EL. Promoting effect of sodium deoxycholate on colon adenocarcinomas in germfree rats. J Natl Cancer Inst. 1976;56:441–442.PubMedGoogle Scholar
  15. 15.
    Ou J, DeLany JP, Zhang M, Sharma S, O’Keefe SJ. Association between low colonic short-chain fatty acids and high bile acids in high colon cancer risk populations. Nutr Cancer. 2012;64:34–40.PubMedCrossRefGoogle Scholar
  16. 16.
    Gordon SJ, Miller LJ, Haeffner LJ, Kinsey MD, Kowlessar OD. Abnormal intestinal bile acid distribution in azotaemic man: a possible role in the pathogenesis of uraemic diarrhoea. Gut. 1976;17:58–67.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47:241–259.PubMedCrossRefGoogle Scholar
  18. 18.
    Bayerdorffer E, Mannes GA, Richter WO, et al. Increased serum deoxycholic acid levels in men with colorectal adenomas. Gastroenterology. 1993;104:145–151.PubMedGoogle Scholar
  19. 19.
    Ochsenkuhn T, Bayerdorffer E, Meining A, et al. Colonic mucosal proliferation is related to serum deoxycholic acid levels. Cancer. 1999;85:1664–1669.PubMedCrossRefGoogle Scholar
  20. 20.
    Bartram HP, Scheppach W, Schmid H, et al. Proliferation of human colonic mucosa as an intermediate biomarker of carcinogenesis: effects of butyrate, deoxycholate, calcium, ammonia, and ph. Cancer Res. 1993;53:3283–3288.PubMedGoogle Scholar
  21. 21.
    Deschner EE, Cohen BI, Raicht RF. Acute and chronic effect of dietary cholic acid on colonic epithelial cell proliferation. Digestion. 1981;21:290–296.PubMedCrossRefGoogle Scholar
  22. 22.
    McMillan L, Butcher S, Wallis Y, Neoptolemos JP, Lord JM. Bile acids reduce the apoptosis-inducing effects of sodium butyrate on human colon adenoma (aa/c1) cells: implications for colon carcinogenesis. Biochem Biophys Res Commun. 2000;273:45–49.PubMedCrossRefGoogle Scholar
  23. 23.
    Earnest DL, Holubec H, Wali RK, et al. Chemoprevention of azoxymethane-induced colonic carcinogenesis by supplemental dietary ursodeoxycholic acid. Cancer Res. 1994;54:5071–5074.PubMedGoogle Scholar
  24. 24.
    Pardi DS, Loftus EV Jr, Kremers WK, Keach J, Lindor KD. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology. 2003;124:889–893.PubMedCrossRefGoogle Scholar
  25. 25.
    Tung BY, Emond MJ, Haggitt RC, et al. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med. 2001;134:89–95.PubMedCrossRefGoogle Scholar
  26. 26.
    Alberts DS, Martinez ME, Hess LM, et al. Phase iii trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. J Natl Cancer Inst. 2005;97:846–853.PubMedCrossRefGoogle Scholar
  27. 27.
    Serfaty L, De Leusse A, Rosmorduc O, et al. Ursodeoxycholic acid therapy and the risk of colorectal adenoma in patients with primary biliary cirrhosis: an observational study. Hepatology. 2003;38:203–209.PubMedCrossRefGoogle Scholar
  28. 28.
    Thompson PA, Wertheim BC, Roe DJ, et al. Gender modifies the effect of ursodeoxycholic acid in a randomized controlled trial in colorectal adenoma patients. Cancer Prev Res (Phila). 2009;2:1023–1030.CrossRefGoogle Scholar
  29. 29.
    Gielen J, Van Cantfort J. Role of bile acids in the regulation of cholesterol 7 alpha-hydroxylase. Arch Int Physiol Biochim. 1969;77:965–966.PubMedGoogle Scholar
  30. 30.
    Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284:1362–1365.PubMedCrossRefGoogle Scholar
  31. 31.
    Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999;284:1365–1368.PubMedCrossRefGoogle Scholar
  32. 32.
    Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous bile acids are ligands for the nuclear receptor fxr/bar. Mol Cell. 1999;3:543–553.PubMedCrossRefGoogle Scholar
  33. 33.
    Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor pxr is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A. 2001;98:3369–3374.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Xie W, Radominska-Pandya A, Shi Y, et al. An essential role for nuclear receptors sxr/pxr in detoxification of cholestatic bile acids. Proc Natl Acad Sci U S A. 2001;98:3375–3380.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Makishima M, Lu TT, Xie W, et al. Vitamin d receptor as an intestinal bile acid sensor. Science. 2002;296:1313–1316.PubMedCrossRefGoogle Scholar
  36. 36.
    Logan CY, Nusse R. The wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810.PubMedCrossRefGoogle Scholar
  37. 37.
    Taketo MM. Shutting down wnt signal-activated cancer. Nat Genet. 2004;36:320–322.PubMedCrossRefGoogle Scholar
  38. 38.
    Pai R, Tarnawski AS, Tran T. Deoxycholic acid activates beta-catenin signaling pathway and increases colon cell cancer growth and invasiveness. Mol Biol Cell. 2004;15:2156–2163.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Wu H, Lin Y, Li W, et al. Regulation of nur77 expression by beta-catenin and its mitogenic effect in colon cancer cells. FASEB J. 2011;25:192–205.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37:S9–S15.PubMedCrossRefGoogle Scholar
  41. 41.
    Lee HY, Crawley S, Hokari R, Kwon S, Kim YS. Bile acid regulates muc2 transcription in colon cancer cells via positive egfr/pkc/ras/erk/creb, pi3 k/akt/ikappab/nf-kappab and p38/msk1/creb pathways and negative jnk/c-jun/ap-1 pathway. Int J Oncol. 2010;36:941–953.PubMedGoogle Scholar
  42. 42.
    Im E, Akare S, Powell A, Martinez JD. Ursodeoxycholic acid can suppress deoxycholic acid-induced apoptosis by stimulating akt/pkb-dependent survival signaling. Nutr Cancer. 2005;51:110–116.PubMedCrossRefGoogle Scholar
  43. 43.
    Saeki T, Yui S, Hirai T, Fujii T, Okada S, Kanamoto R. Ursodeoxycholic acid protects colon cancer hct116 cells from deoxycholic acid-induced apoptosis by inhibiting apoptosome formation. Nutr Cancer. 2012;64:617–626.PubMedCrossRefGoogle Scholar
  44. 44.
    Raufman JP, Shant J, Guo CY, Roy S, Cheng K. Deoxycholyltaurine rescues human colon cancer cells from apoptosis by activating egfr-dependent pi3 k/akt signaling. J Cell Physiol. 2008;215:538–549.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Shant J, Cheng K, Marasa BS, Wang JY, Raufman JP. Akt-dependent nf-kappab activation is required for bile acids to rescue colon cancer cells from stress-induced apoptosis. Exp Cell Res. 2009;315:432–450.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Cheng K, Xie G, Raufman JP. Matrix metalloproteinase-7-catalyzed release of hb-egf mediates deoxycholyltaurine-induced proliferation of a human colon cancer cell line. Biochem Pharmacol. 2007;73:1001–1012.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Khare S, Mustafi R, Cerda S, et al. Ursodeoxycholic acid suppresses cox-2 expression in colon cancer: roles of ras, p38, and ccaat/enhancer-binding protein. Nutr Cancer. 2008;60:389–400.PubMedCrossRefGoogle Scholar
  48. 48.
    Im E, Martinez JD. Ursodeoxycholic acid (udca) can inhibit deoxycholic acid (dca)-induced apoptosis via modulation of egfr/raf-1/erk signaling in human colon cancer cells. J Nutr. 2004;134:483–486.PubMedGoogle Scholar
  49. 49.
    Shah SA, Volkov Y, Arfin Q, Abdel-Latif MM, Kelleher D. Ursodeoxycholic acid inhibits interleukin beta 1 and deoxycholic acid-induced activation of nf-κb and ap-1 in human colon cancer cells. Int J Cancer. 2006;118:532–539.PubMedCrossRefGoogle Scholar
  50. 50.
    Yoo J, Rodriguez Perez CE, Nie W, Edwards RA, Sinnett-Smith J, Rozengurt E. Tnf-alpha induces upregulation of egfr expression and signaling in human colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol. 2012;302:G805–G814.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Hobbs SS, Goettel JA, Liang D, et al. Tnf transactivation of egfr stimulates cytoprotective cox-2 expression in gastrointestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2011;301:G220–G229.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Qiao D, Gaitonde SV, Qi W, Martinez JD. Deoxycholic acid suppresses p53 by stimulating proteasome-mediated p53 protein degradation. Carcinogenesis. 2001;22:957–964.PubMedCrossRefGoogle Scholar
  53. 53.
    Song S, Byrd JC, Koo JS, Bresalier RS. Bile acids induce muc2 overexpression in human colon carcinoma cells. Cancer. 2005;103:1606–1614.PubMedCrossRefGoogle Scholar
  54. 54.
    Powell AA, Akare S, Qi W, et al. Resistance to ursodeoxycholic acid-induced growth arrest can also result in resistance to deoxycholic acid-induced apoptosis and increased tumorigenicity. BMC Cancer. 2006;6:219.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Qiao D, Chen W, Stratagoules ED, Martinez JD. Bile acid-induced activation of activator protein-1 requires both extracellular signal-regulated kinase and protein kinase c signaling. J Biol Chem. 2000;275:15090–15098.PubMedCrossRefGoogle Scholar
  56. 56.
    Shah SA, Looby E, Volkov Y, Long A, Kelleher D. Ursodeoxycholic acid inhibits translocation of protein kinase c in human colonic cancer cell lines. Eur J Cancer. 2005;41:2160–2169.PubMedCrossRefGoogle Scholar
  57. 57.
    Shah SA, Mahmud N, Mftah M, Roche HM, Kelleher D. Chronic but not acute conjugated linoleic acid treatment inhibits deoxycholic acid-induced protein kinase c and nuclear factor-kappab activation in human colorectal cancer cells. Eur J Cancer Prev. 2006;15:125–133.PubMedCrossRefGoogle Scholar
  58. 58.
    Qiao L, Studer E, Leach K, et al. Deoxycholic acid (dca) causes ligand-independent activation of epidermal growth factor receptor (egfr) and fast receptor in primary hepatocytes: inhibition of egfr/mitogen-activated protein kinase-signaling module enhances dca-induced apoptosis. Mol Biol Cell. 2001;12:2629–2645.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Rao YP, Studer EJ, Stravitz RT, et al. Activation of the raf-1/mek/erk cascade by bile acids occurs via the epidermal growth factor receptor in primary rat hepatocytes. Hepatology. 2002;35:307–314.PubMedCrossRefGoogle Scholar
  60. 60.
    Yoon JH, Higuchi H, Werneburg NW, Kaufmann SH, Gores GJ. Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line. Gastroenterology. 2002;122:985–993.PubMedCrossRefGoogle Scholar
  61. 61.
    Werneburg NW, Yoon JH, Higuchi H, Gores GJ. Bile acids activate egf receptor via a tgf-alpha-dependent mechanism in human cholangiocyte cell lines. Am J Physiol Gastrointest Liver Physiol. 2003;285:G31–G36.PubMedGoogle Scholar
  62. 62.
    Yoon JH, Werneburg NW, Higuchi H, et al. Bile acids inhibit mcl-1 protein turnover via an epidermal growth factor receptor/raf-1-dependent mechanism. Cancer Res. 2002;62:6500–6505.PubMedGoogle Scholar
  63. 63.
    Goldman A, Chen HD, Roesly HB, et al. Characterization of squamous esophageal cells resistant to bile acids at acidic ph: implication for barrett’s esophagus pathogenesis. Am J Physiol Gastrointest Liver Physiol. 2011;300:G292–G302.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Avissar NE, Toia L, Hu Y, et al. Bile acid alone, or in combination with acid, induces cdx2 expression through activation of the epidermal growth factor receptor (egfr). J Gastrointest Surg. 2009;13:212–222.PubMedCrossRefGoogle Scholar
  65. 65.
    Yasuda H, Hirata S, Inoue K, Mashima H, Ohnishi H, Yoshiba M. Involvement of membrane-type bile acid receptor m-bar/tgr5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells. Biochem Biophys Res Commun. 2007;354:154–159.PubMedCrossRefGoogle Scholar
  66. 66.
    Qiao D, Stratagouleas ED, Martinez JD. Activation and role of mitogen-activated protein kinases in deoxycholic acid-induced apoptosis. Carcinogenesis. 2001;22:35–41.PubMedCrossRefGoogle Scholar
  67. 67.
    Keating N, Mroz MS, Scharl MM, et al. Physiological concentrations of bile acids down-regulate agonist induced secretion in colonic epithelial cells. J Cell Mol Med. 2009;13:2293–2303.PubMedCrossRefGoogle Scholar
  68. 68.
    Akare S, Martinez JD. Bile acid induces hydrophobicity-dependent membrane alterations. Biochim Biophys Acta. 2005;1735:59–67.PubMedCrossRefGoogle Scholar
  69. 69.
    Rao YP, Stravitz RT, Vlahcevic ZR, Gurley EC, Sando JJ, Hylemon PB. Activation of protein kinase c alpha and delta by bile acids: correlation with bile acid structure and diacylglycerol formation. J Lipid Res. 1997;38:2446–2454.PubMedGoogle Scholar
  70. 70.
    Looby E, Long A, Kelleher D, Volkov Y. Bile acid deoxycholate induces differential subcellular localisation of the pkc isoenzymes beta 1, epsilon and delta in colonic epithelial cells in a sodium butyrate insensitive manner. Int J Cancer. 2005;114:887–895.PubMedCrossRefGoogle Scholar
  71. 71.
    Fang Y, Han SI, Mitchell C, et al. Bile acids induce mitochondrial ros, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. Hepatology. 2004;40:961–971.PubMedCrossRefGoogle Scholar
  72. 72.
    Cronin J, Williams L, McAdam E, et al. The role of secondary bile acids in neoplastic development in the oesophagus. Biochem Soc Trans. 2010;38:337–342.PubMedCrossRefGoogle Scholar
  73. 73.
    Jenkins GJS, D’Souza FR, Suzen SH, et al. Deoxycholic acid at neutral and acid ph, is genotoxic to oesophageal cells through the induction of ROS: the potential role of anti-oxidants in Barrett’s oesophagus. Carcinogenesis. 2006;28:136–142.Google Scholar
  74. 74.
    Ignacio Barrasa J, Olmo N, Perez-Ramos P, et al. Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells. Apoptosis. 2011;16:1054–1067.PubMedCrossRefGoogle Scholar
  75. 75.
    Feldman R, Martinez JD. Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of egfr. Biochim Biophys Acta. 2009;1793:1387–1394.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Ha YH, Park DG. Effects of dca on cell cycle proteins in colonocytes. J Korean Soc Coloproctol. 2010;26:254–259.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Mason RP, Moisey DM, Shajenko L. Cholesterol alters the binding of ca2 + channel blockers to the membrane lipid bilayer. Mol Pharmacol. 1992;41:315–321.PubMedGoogle Scholar
  78. 78.
    Smith AF, Longpre J, Loo G. Inhibition by zinc of deoxycholate-induced apoptosis in hct-116 cells. J Cell Biochem. 2012;113:650–657.PubMedCrossRefGoogle Scholar
  79. 79.
    Longpre J, Loo G. Inhibition of deoxycholate-induced apoptosis in iron-depleted hct-116 cells. Apoptosis. 2012;17:70–78.PubMedCrossRefGoogle Scholar
  80. 80.
    Di Toro R, Campana G, Murari G, Spampinato S. Effects of specific bile acids on c-fos messenger rna levels in human colon carcinoma caco-2 cells. Eur J Pharm Sci. 2000;11:291–298.PubMedCrossRefGoogle Scholar
  81. 81.
    Kim HS, Lee YK, Kim JW, Baik SK, Kwon SO, Jang HI. Modulation of colon cancer cell invasiveness induced by deoxycholic acid. Korean J Gastroenterol. 2006;48:9–18.PubMedGoogle Scholar
  82. 82.
    Lee DK, Park SY, Baik SK, et al. Deoxycholic acid-induced signal transduction in ht-29 cells: role of nf-kappa b and interleukin-8. Korean J Gastroenterol. 2004;43:176–185.PubMedGoogle Scholar
  83. 83.
    Zeng H, Botnen JH, Briske-Anderson M. Deoxycholic acid and selenium metabolite methylselenol exert common and distinct effects on cell cycle, apoptosis, and map kinase pathway in hct116 human colon cancer cells. Nutr Cancer. 2009;62:85–92.CrossRefGoogle Scholar
  84. 84.
    McMillan L, Butcher SK, Pongracz J, Lord JM. Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma cells: differential activation of pkc and map kinases. Br J Cancer. 2003;88:748–753.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Krishna-Subramanian S, Hanski ML, Loddenkemper C, et al. Udca slows down intestinal cell proliferation by inducing high and sustained erk phosphorylation. Int J Cancer. 2012;130:2771–2782.PubMedCrossRefGoogle Scholar
  86. 86.
    Miyaki A, Yang P, Tai H-H, Subbaramaiah K, Dannenberg AJ. Bile acids inhibit nad + -dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes. Am J Physiol Gastrointest Liver Physiol. 2009;297:G559–G566.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Merchant NB, Rogers CM, Trivedi B, Morrow J, Coffey RJ. Ligand-dependent activation of the epidermal growth factor receptor by secondary bile acids in polarizing colon cancer cells. Surgery. 2005;138:415–421.PubMedCrossRefGoogle Scholar
  88. 88.
    Akare S, Jean-Louis S, Chen W, Wood DJ, Powell AA, Martinez JD. Ursodeoxycholic acid modulates histone acetylation and induces differentiation and senescence. Int J Cancer. 2006;119:2958–2969.PubMedCrossRefGoogle Scholar
  89. 89.
    Da Silva M, Jaggers GK, Verstraeten SV, Erlejman AG, Fraga CG, Oteiza PI. Large procyanidins prevent bile-acid-induced oxidant production and membrane-initiated erk1/2, p38, and akt activation in caco-2 cells. Free Radic Biol Med. 2012;52:151–159.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Cellular and Molecular MedicineThe University of Arizona Cancer CenterTucsonUSA

Personalised recommendations