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Bile acids stimulate invasion and haptotaxis in human colorectal cancer cells through activation of multiple oncogenic signaling pathways

Oncogene volume 21, pages 6740–6750 (2002)Cite this article

Abstract

Bile acids are implicated in colorectal carcinogenesis as evidenced by epidemiological and experimental studies. We examined whether bile acids stimulate cellular invasion of human colorectal and dog kidney epithelial cells at different stages of tumor progression. Colon PC/AA/C1, PCmsrc, and HCT-8/E11 cells and kidney MDCKT23 cells were seeded on top of collagen type I gels and invasive cells were counted after 24 h incubation. Activation of the Rac1 and RhoA small GTPases was investigated by pull-down assays. Haptotaxis was analysed with modified Boyden chambers. Lithocholic acid, chenodeoxycholic acid, cholic acid and deoxycholic acid stimulated cellular invasion of SRC- and RhoA-transformed PCmsrc and MDCKT23-RhoAV14 cells, and of HCT-8/E11 cells originating from a sporadic tumor, but were ineffective in premalignant PC/AA/C1 and MDCKT23 cells. Bile acid-stimulated invasion occurred through stimulation of haptotaxis and was dependent on the RhoA/Rho-kinase pathway and signaling cascades using protein kinase C, mitogen-activated protein kinase, and cyclooxygenase-2. Accordingly, BA-induced invasion was associated with activation of the Rac1 and RhoA GTPases and expression of the farnesoid X receptor. We conclude that bile acids stimulate invasion and haptotaxis in colorectal cancer cells via several cancer invasion signaling pathways.

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References

  • André F, Rigot V, Thimonier J, Montixi C, Parat F, Pommier G, Marvaldi J, Luis J . 1999 Int. J. Cancer 83: 497–505

  • Attoub S, Noë V, Pirola L, Bruyneel E, Chastre E, Mareel M, Wymann MP, Gespach C . 2000 FASEB J. 14: 2329–2338

  • Aznavoorian S, Liotta LA, Kupchik HZ . 1990 J. Natl. Cancer Inst. 82: 1485–1492

  • Batlle E, Verdú J, Dominguez D, del Mont Llosas M, Diaz V, Loukili N, Paciucci R, Alameda F, Garcia de Herreros A . 1998 J. Biol. Chem. 273: 15091–15098

  • Batta AK, Salen G, Holubec H, Brasitus TA, Alberts D, Earnest DL . 1998 Cancer Res. 58: 1684–1687

  • Bayerdörffer E, Mannes GA, Richter WO, Ochsenkühn T, Wiebecke B, Köpcke W, Paumgartner G . 1993 Gastroenterology 104: 145–151

  • Bracke ME, Depypere H, Labit C, Van Marck V, Vennekens K, Vermeulen SJ, Maelfait I, Philippé J, Serreyn R, Mareel MM . 1997 Eur. J. Cell. Biol. 74: 342–349

  • Bracke ME, Vyncke BM, Bruyneel EA, Vermeulen SJ, De Bruyne GK, Van Larebeke NA, Vleminckx K, Van Roy FM, Mareel MM . 1993 Br. J. Cancer 68: 282–289

  • Chang J-H, Pratt JC, Sawasdikosol S, Kapeller R, Burakoff SJ . 1998 Mol. Cell. Biol. 18: 4986–4993

  • Dannenberg AJ, Zakim D . 1999 Sem. Oncol. 26: 499–504

  • Earnest DL, Holubec H, Wali RK, Jolley CS, Bissonette M, Bhattacharyya AK, Roy H, Khare S, Brasitus TA . 1994 Cancer Res. 54: 5071–5074

  • Emami S, Le Floch N, Bruyneel E, Thim L, May F, Westley B, Rio M-C, Mareel M, Gespach C . 2001 FASEB J. 15: 351–361

  • Empereur S, Djelloul S, Di Gioia Y, Bruyneel E, Mareel M, Van Hengel J, Van Roy F, Comoglio P, Courtneidge S, Paraskeva C, Chastre E, Gespach C . 1997 Br. J. Cancer 75: 241–250

  • Fujita T, Matsui M, Takaku K, Uetake H, Ichikawa W, Taketo MM, Sugihara K . 1998 Cancer Res. 58: 4823–4826

  • Glinghammar B, Rafter J . 2001 Gastroenterology 120: 401–410

  • Gupta S, Stravitz RT, Dent P, Hylemon PB . 2001 J. Biol. Chem. 276: 15816–15822

  • Hall A . 1998 Science 279: 509–514

  • Halvorsen B, Staff AC, Ligaarden S, Prydz K, Kolset SO . 2000 Biochem. J. 349: 189–193

  • Hennigan RF, Hawker KL, Ozanne BW . 1994 Oncogene 9: 3591–3600

  • Hill MJ, Drasar BS, Aries V, Crowther JS, Hawksworth G, Williams REO . 1971 Lancet 1: 95–100

  • Hirano F, Tanaka H, Makino Y, Okamoto K, Hiramoto M, Handa H, Makino I . 1996 Carcinogenesis 17: 427–433

  • Hofmann J . 1997 FASEB J. 11: 649–669

  • Huang XP, Fan XT, Desjeux JF, Castagna M . 1992 Int. J. Cancer 52: 444–450

  • Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, Karl R, Fujita DJ, Jove R, Yeatman TJ . 1999 Nat. Genet. 21: 187–190

  • Jou T-S, Nelson WJ . 1998 J. Cell. Biol. 142: 85–100

  • Kamano T, Mikami Y, Kurasawa T, Tsurumaru M, Matsumoto M, Kano M, Motegi K . 1999 Dis. Colon Rectum 42: 668–672

  • Kotelevets L, Noë V, Bruyneel E, Myssiakine E, Chastre E, Mareel M, Gespach C . 1998 J. Biol. Chem. 273: 14138–14145

  • Kozoni V, Tsioulias G, Shiff S, Rigas B . 2000 Carcinogenesis 21: 999–1005

  • Kurtz W . 1992 Verdauungskrankheiten 10: 153–162

  • Kurz AC, Block C, Graf D, vom Dahl S, Schliess F, Häussinger D . 2000 Biochem. J. 350: 207–213

  • Kustikova O, Kramerov D, Grigorian M, Berezin V, Bock E, Lukanidin E, Tulchinsky E . 1998 Mol. Cell. Biol. 18: 7095–7105

  • Latta RK, Fiander H, Ross NW, Simpson C, Schneider H . 1993 Cancer Lett. 70: 167–173

  • Lehmann M, Rabenandrasana C, Tamura R, Lissitzky J-C, Quaranta V, Pichon J, Marvaldi J . 1994 Cancer Res. 54: 2102–2107

  • Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B . 1999 Science 284: 1362–1365

  • Mareel M, Berx G, Van Roy F, Bracke M . 1996 J. Cell Biochem. 61: 524–530

  • McMichael AJ, Potter JD . 1985 J. Natl. Cancer Inst. 75: 185–191

  • McMillan L, Butcher S, Wallis Y, Neoptolemos JP, Lord JM . 2000 Biochem. Biophys. Res. Commun. 273: 45–49

  • Moseley RH . 1999 Textbook of Gastroenterology 3rd edn Chapter 17 Yamada T (eds) Alpers DH, Owyang C, Laine L and Powell DW (ass. eds) Philadelphia, New York, Baltimore: Lippincott Williams & Wilkins pp. 380–403

    Google Scholar 

  • Nagengast FM, Grubben MJAL, van Munster IP . 1995 Eur. J. Cancer 31A: 1067–1070

  • Narisawa T, Magadia NE, Weisburger JH, Wynder EL . 1974 J. Natl. Cancer Inst. 53: 1093–1097

  • Owen RW . 1997 Scand. J. Gastroenterol. Suppl 222: 76–82

  • Ozanne BW, McGarry L, Spence HJ, Johnston I, Winnie J, Meagher L, Stapleton G . 2000 Eur. J. Cancer 36: 1640–1648

  • Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM . 1999 Science 284: 1365–1368

  • Pongracz J, Clark P, Neoptolemos JP, Lord JM . 1995 Int. J. Cancer 61: 35–39

  • Qiao D, Chen W, Stratagoules ED, Martinez JD . 2000 J. Biol. Chem. 275: 15090–15098

  • Qiao D, Stratagouleas ED, Martinez JD . 2001 Carcinogenesis 22: 35–41

  • Rao Y-P, Stravitz RT, Vlahcevic ZR, Gurley EC, Sando JJ, Hylemon PB . 1997 J. Lipid. Res. 38: 2446–2454

  • Reddy BS . 1981 Cancer Res. 41: 3766–3768

  • Reddy BS, Watanabe K, Weisburger JH, Wynder EL . 1977 Cancer Res. 37: 3228–3242

  • Rodrigues S, Nguyen Q-D, Faivre S, Bruyneel E, Thim L, Westley B, May F, Flatau G, Mareel M, Gespach C, Emami S . 2001 FASEB J. 15: 1517–1528

  • Rust C, Karnitz LM, Paya CV, Moscat J, Simari RD, Gores GJ . 2000 J. Biol. Chem. 275: 20210–20216

  • Sander EE, Collard JG . 1999 Eur. J. Cancer 35: 1302–1308

  • Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JG . 1999 J. Cell. Biol. 147: 1009–1021

  • Sander EE, van Delft S, ten Klooster JP, Reid T, van der Kammen RA, Michiels F, Collard JG . 1998 J. Cell. Biol. 143: 1385–1398

  • Schlottmann K, Wachs F-P, Krieg RC, Kullmann F, Schölmerich J, Rogler G . 2000 Cancer Res. 60: 4270–4276

  • Shimao Y, Nabeshima K, Inoue T, Koono M . 1999 Clin. Exp. Metastasis 17: 351–360

  • Slice LW, Bui L, Mak C, Walsh JH . 2000 Biochem. Biophys. Res. Commun. 276: 406–410

  • Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM, Koller BH, Kliewer SA . 2001 Proc. Natl. Acad. Sci. USA 98: 3369–3374

  • Summerton J, Flynn M, Cooke T, Taylor I . 1983 Br. J. Surg. 70: 549–551

  • Tsujii M, Kawano S, DuBois RN . 1997 Proc. Natl. Acad. Sci. USA 94: 3336–3340

  • Vakaet Jr L, Vleminckx K, Van Roy F, Mareel M . 1991 Invasion Metastasis 11: 249–260

  • Vermeulen SJ, Bruyneel EA, Bracke ME, De Bruyne GK, Vennekens KM, Vleminckx KL, Berx GJ, Van Roy FM, Mareel MM . 1995 Cancer Res. 55: 4722–4728

  • Vermeulen SJ, Nollet F, Teugels E, Vennekens KM, Malfait F, Philippé J, Speleman F, Bracke ME, Van Roy FM, Mareel MM . 1999 Oncogene 18: 905–915

  • Wang H, Chen J, Hollister K, Sowers LC, Forman BM . 1999 Mol. Cell 3: 543–553

  • Willett WC, Stamper MJ, Colditz GA, Rosner BA, Speizer FE . 1990 N. Engl. J. Med. 323: 1664–1672

  • Williams AC, Harper SJ, Paraskeva C . 1990 Cancer Res. 50: 4724–4730

  • Xie W, Radominska-Pandya A, Shi Y, Simon CM, Nelson MC, Ong ES, Waxman DJ, Evans RM . 2001 Proc. Natl. Acad. Sci. USA 98: 3375–3380

  • Zhang F, Subbaramaiah K, Altorki N, Dannenberg AJ . 1998 J. Biol. Chem. 273: 2424–2428

  • Zimber A, Chedeville A, Abita J-P, Barbu V, Gespach C . 2000 Cancer Res. 60: 672–678

  • Zondag GCM, Evers EE, ten Klooster JP, Janssen L, van der Kammen RA, Collard JG . 2000 J. Cell. Biol. 149: 775–781

Download references

Acknowledgements

We thank L Baeke, R Colman, G Desmet, G De Bruyne and A Verspeelt for technical assistance, Dr F André and Dr T Boterberg (Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium) and Dr V Rigot (Unité de Biologie Cellulaire, Université Catholique de Louvain, Brussels, Belgium) for helpful suggestions, and Dr J-C Lissitzky (Laboratoire de Biochimie Cellulaire, CNRS, Marseille, France) for providing the antibody against αV integrin.

This work was supported by the ‘FWO-Vlaanderen’ (Brussels, Belgium), the ‘Sportvereniging tegen Kanker’ (Brussels, Belgium), the ‘ASLK/VIVA-verzekeringen’ (Brussels, Belgium), the ‘G.O.A. from the Vlaamse Gemeenschap’ (Brussels, Belgium), INSERM and ARC (France) and the ‘Deutsche Krebshilfe e.V.’ (Bonn, Germany). Ph. Debruyne is a Research Assistant with the ‘Bijzonder Onderzoeksfonds Universiteit Gent’ (Ghent, Belgium).

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Authors and Affiliations

  1. Department of Radiotherapy and Nuclear Medicine, Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, B-9000, Belgium

    P R Debruyne, E A Bruyneel, Xd Li & M M Mareel

  2. Max-Planck-Institut für molekulare Physiologie, Dortmund, 44227, Germany

    I-M Karaguni & O Müller

  3. INSERM U 452, Biologie Cellulaire et Moléculaire des Microorganismes Pathogènes et de leurs Toxines, UFR de Médecine, Nice Cedex, 06107, France

    G Flatau

  4. INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, Paris, 75571, Cedex 12, France

    A Zimber & C Gespach

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Correspondence to M M Mareel.

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Debruyne, P., Bruyneel, E., Karaguni, IM. et al. Bile acids stimulate invasion and haptotaxis in human colorectal cancer cells through activation of multiple oncogenic signaling pathways. Oncogene 21, 6740–6750 (2002). https://doi.org/10.1038/sj.onc.1205729

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