Advertisement

Digestive Diseases and Sciences

, Volume 52, Issue 1, pp 240–247 | Cite as

Rebamipide Inhibits Gastric Cancer Cell Growth

  • Tetsuya Tanigawa
  • Rama Pai
  • Tetsuo Arakawa
  • Andrzej S. Tarnawski
Original Paper

Abstract

Rebamipide is an antiulcer drug used in Japan, Korea, China, Philippines, and other Asian countries for treatment of gastritis and peptic ulcer. Its effect on gastric cancer cell growth and its regulatory mechanisms remain unknown. We examined whether rebamipide affects human gastric cancer cell proliferation and activation of Smad signaling pathway. Gastric cancer (AGS) cells were treated with either (a) medium (control), (b) medium-containing rebamipide (0.5–2 mg/mL), or (c) PD98059+rebamipide. We determined cell proliferation, expression of p21, phosphorylation of ERK2, JNK p38, and Smad2/3, formation of Smad2/3–Smad4 complex, and nuclear translocation of Smad2/3. Rebamipide treatment inhibited AGS cell proliferation and increased p21, Smad2/3 phosphorylation, and Smad2/3–Smad4 complex formation. Rebamipide induced phosphorylation of ERK2 but not JNK or p38. Inactivation of ERK2 by PD98059 partly attenuated rebamipide-induced p21 expression. These data demonstrate that rebamipide activates Smad signaling pathway and suppresses human gastric cancer cell growth. Inactivation of ERK2 partly inhibited rebamipide-induced p21 expression, indicating a crosstalk between ERK and Smad signaling pathways.

Keywords

Gastric cancer Rebamipide Cyclin-dependent kinases Smad signaling pathway MAP kinase 

References

  1. 1.
    Parkin DM, Pisani P, Ferlay J (1993) Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 54:594–606CrossRefPubMedGoogle Scholar
  2. 2.
    Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr (1991) Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265:1287–1289CrossRefPubMedGoogle Scholar
  3. 3.
    Howson CP, Hiyama T, Wynder EL (1986) The decline in gastric cancer; epidemiology of an unplanned triumph. Epidemiol Rev 8:1–27PubMedGoogle Scholar
  4. 4.
    Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process-First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52:6735–6740PubMedGoogle Scholar
  5. 5.
    Maruyama M (1998) Treatment results of gastric cancer staged by the TNM classification. In Maruyama M, Kimura K (eds) Reviews of clinical research in gastroenterology. Tokyo, Igaku-Shoin, pp 112–126Google Scholar
  6. 6.
    Sherr CJ (2000) The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 60:3689–3695PubMedGoogle Scholar
  7. 7.
    Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF (1995) Transforming growth factor β induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci USA 92:5545–5549CrossRefPubMedGoogle Scholar
  8. 8.
    Hannon GJ, Beach D (1994) p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 371:257–261, 1994CrossRefPubMedGoogle Scholar
  9. 9.
    Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A (1994) p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest. Genes Dev 8:9–22CrossRefPubMedGoogle Scholar
  10. 10.
    Reynisdottir I, Polyak K, Iavarone A, Massague J (1995) Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-β. Genes Dev 9:1831–1845CrossRefPubMedGoogle Scholar
  11. 11.
    Attisano L, Wrana JL (2002) Signal transduction by the TGF-β superfamily. Science 296:1646–1647CrossRefPubMedGoogle Scholar
  12. 12.
    Brown JD, DiChiara MR, Anderson KR, Gimbrone MA Jr, Topper JN (1999) MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway can selectively activate Smad2-mediated transcriptional activation in endothelial cells. J Biol Chem 274:8797–8805CrossRefPubMedGoogle Scholar
  13. 13.
    de Caestecker MP, Parks WT, Frank CJ, Castagnino P, Bottaro DP, Roberts AB, Lechleider RJ (1998) Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. Genes Dev 12:1587–1592PubMedGoogle Scholar
  14. 14.
    Hayashida T, Decaestecker M, Schnaper HW (2003) Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-β-dependent responses in human mesangial cells. FASEB J 17:1576–1578PubMedGoogle Scholar
  15. 15.
    Hayes SA, Huang X, Kambhampati S, Platanias LC, Bergan RC (2003) MAP kinase modulates Smad-dependent changes in human prostate cell adhesion. Oncogene 22:4841–4850CrossRefPubMedGoogle Scholar
  16. 16.
    Heldin CH, Miyazono K, ten Dijke P (1997) TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471CrossRefPubMedGoogle Scholar
  17. 17.
    Moustakas A, Kardassis D (1998) Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members. Proc Natl Acad Sci U S A 95:6733–6738CrossRefPubMedGoogle Scholar
  18. 18.
    Pardali K, Kurisaki A, Moren A, ten Dijke P, Kardassis D, Moustakas A (2000) Role of Smad proteins and transcription factor Sp1 in p21(Waf1/Cip1) regulation by transforming growth factor-β. J Biol Chem 275:29244–29256CrossRefPubMedGoogle Scholar
  19. 19.
    Shen X, Hu PP, Liberati NT, Datto MB, Frederick JP, Wang XF (1998) TGF-β-induced phosphorylation of Smad3 regulates its interaction with coactivator p300/CREB-binding protein. Mol Biol Cell 9:3309–3319PubMedGoogle Scholar
  20. 20.
    Arakawa T, Kobayashi K, Yoshikawa T, Tarnawski A (1998) Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Dig Dis Sci 43(9 Suppl):5S–13SPubMedGoogle Scholar
  21. 21.
    Arakawa T, Watanabe T, Fukuda T, Yamasaki K, Kobayashi K (1995) Rebamipide, novel prostaglandin-inducer accelerates healing and reduces relapse of acetic acid-induced rat gastric ulcer. Comparison with cimetidine. Dig Dis Sci 40:2469–2472Google Scholar
  22. 22.
    Ogino K, Hobara T, Ishiyama H, Yamasaki K, Kobayashi H, Izumi Y, Oka S (1992) Antiulcer mechanism of action of Rebamipide, a novel antiulcer compound, on diethyldithiocarbamate-induced antral gastric ulcers rats. Eur J Pharmacol 212:219–213CrossRefGoogle Scholar
  23. 23.
    Tarnawski A, Arakawa T, Kobayashi K (1998) Rebamipide treatment activates epidermal growth factors and its receptor expression in normal and ulcerated gastric mucosa in rats: one mechanism for its ulcer healing action? Dig Dis Sci 43(9 Suppl):90S–98SPubMedGoogle Scholar
  24. 24.
    Kleine A, Kluge S, Peskar BM (1993) Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of Rebamipide in rats. Dig Dis Sci 38:1441–1449CrossRefPubMedGoogle Scholar
  25. 25.
    Murakami K, Okajima K, Uchiba M, Harada N, Johno M, Okabe H, Takatsuki K (1997) Rebamipide attenuates indomethacin-induced gastric mucosal lesion formation by inhibiting activation of leukocytes in rats. Dig Dis Sci 42:319–325CrossRefPubMedGoogle Scholar
  26. 26.
    Naito Y, Yoshikawa T, Tanigawa T, Sakurai K, Yamasaki K, Uchida M, Kondo M (1995) Hydroxyl radical scavenging by Rebamipide and related compounds: electron paramagnetic resonance study. Free Radic Biol Med 18:117–123CrossRefPubMedGoogle Scholar
  27. 27.
    Sakurai K, Yamasaki K (1994) Protective effect of Rebamipide against hydrogen peroxide-induced hemorrhagic mucosal lesions in rat stomach. Jpn J Pharmacol 64:229–234PubMedGoogle Scholar
  28. 28.
    Yoshida N, Yoshikawa T, Iinuma S, Arai M, Takenaka S, Sakamoto K, Miyajima T, Nakamura Y, Yagi N, Naito Y, Mukai F, Kondo M (1996) Rebamipide protects against activation of neutrophils by Helicobacter pylori. Dig Dis Sci 41:1139–1144CrossRefPubMedGoogle Scholar
  29. 29.
    Yamane T, Nakatani H, Matsumoto H, Iwata Y, Kikuoka N, Takahashi T (1998) Inhibitory effects of Rebamipide on ENNG-induced duodenal carcinogenesis in mice: a possible strategy for chemoprevention of gastrointestinal cancers. Dig Dis Sci 43(9 Suppl):207S–211SPubMedGoogle Scholar
  30. 30.
    Tarnawski A, PaiR, Chiou SK, Chai J, Chu EC (2005) Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B. Biochem Biophys Res Commun 334:207–212Google Scholar
  31. 31.
    Fujiwara Y, Schmassmann A, Arakawa T, Halter F, Tarnawski A (1995) Indomethacin interferes with epidermal growth factor binding and proliferative response of gastric KATO III cells. Digestion 56:364–369PubMedCrossRefGoogle Scholar
  32. 32.
    Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D, Tarnawski AS (2002) Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 8:289–293CrossRefPubMedGoogle Scholar
  33. 33.
    Aoyagi K, Koufuji K, Yano S, Murakami N, Miyagi M, Koga A, Takeda J, Shirouzu K (2003) The expression of p53, p21 and TGFβ1 in gastric carcinoma. Kurume Med J 50:1–7PubMedGoogle Scholar
  34. 34.
    Liu XP, Kawauchi S, Oga A, Suehiro Y, Tsushimi K, Tsushimi M, Sasaki K (2001) Combined examination of p27(Kip1), p21(Waf1/Cip1) and p53 expression allows precise estimation of prognosis in patients with gastric carcinoma. Histopathology 39:603–610CrossRefPubMedGoogle Scholar
  35. 35.
    Noda H, Maehara Y, Irie K, Kakeji Y, Yonemura T, Sugimachi K (2002) Increased proliferative activity caused by loss of p21 (WAF1/CIP1) expression and its clinical significance in patients with early-stage gastric carcinoma. Cancer 94:2107–2112CrossRefPubMedGoogle Scholar
  36. 36.
    Ogawa M, Onoda N, Maeda K, Kato Y, Nakata B, Kang SM, Sowa M, Hirakawa K (2001) A combination analysis of p53 and p21 in gastric carcinoma as a strong indicator for prognosis. Int J Mol Med 7:479–483PubMedGoogle Scholar
  37. 37.
    Kralj M, Pavelic J (2003) p21WAF1/CIP1 is more effective than p53 in growth suppression of mouse renal carcinoma cell line Renca in vitro and in vivo. J Cancer Res Clin Oncol 129:463–471CrossRefPubMedGoogle Scholar
  38. 38.
    Shibata MA, Yoshidome K, Shibata E, Jorcyk CL, Green JE (2001) Suppression of mammary carcinoma growth in vitro and in vivo by inducible expression of the Cdk inhibitor p21. Cancer Gene Ther 8:23–35CrossRefPubMedGoogle Scholar
  39. 39.
    Ijichi H, Ikenoue T, Kato N, Mitsuno Y, Togo G, Kato J, Kanai F, Shiratori Y, Omata M (2001) Systematic analysis of the TGF-beta-Smad signaling pathway in gastrointestinal cancer cells. Biochem Biophys Res Commun 289:350–357CrossRefPubMedGoogle Scholar
  40. 40.
    Kretzschmar M, Doody J, Timokhina I, Massague J (1999) A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev 13:804–816PubMedGoogle Scholar
  41. 41.
    Calonge MJ, Massague J (1999) Smad4/DPC4 silencing and hyperactive Ras jointly disrupt transforming growth factor-beta antiproliferative responses in colon cancer cells. J Biol Chem 274:33637–33643CrossRefPubMedGoogle Scholar
  42. 42.
    Blanchette F, Rivard N, Rudd P, Grondin F, Attisano L, Dubois CM (2001) Cross-talk between the p42/p44 MAP kinase and Smad pathways in transforming growth factor beta 1-induced furin gene transactivation. J Biol Chem 276:33986–33994CrossRefPubMedGoogle Scholar
  43. 43.
    Watanabe H, de Caestecker MP, Yamada Y (2001) Transcriptional cross-talk between Smad, ERK1/2, and p38 mitogen-activated protein kinase pathways regulates transforming growth factor-beta-induced aggrecan gene expression in chondrogenic ATDC5 cells. J Biol Chem 276:14466–14473PubMedGoogle Scholar
  44. 44.
    Akamatsu T, Nakamura N, Furuya N, Shimizu T, Gotou A, Kiyosawa K, Katsuyama T, Osumi T, Hirao Y, Miyamoto G (2002) Local gastric and serum concentrations of rebamipide following oral ingestion in healthy volunteers. Dig Dis Sci 47:1399–1404CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Tetsuya Tanigawa
    • 1
    • 2
    • 3
  • Rama Pai
    • 1
    • 2
  • Tetsuo Arakawa
    • 3
  • Andrzej S. Tarnawski
    • 1
    • 2
    • 4
  1. 1.Medical ServiceDepartment of Veterans Affairs Medical CenterLong BeachUSA
  2. 2.Department of MedicineUniversity of CaliforniaIrvineUSA
  3. 3.Department of GastroenterologyOsaka City University Graduate School of MedicineOsakaJapan
  4. 4.Division of GastroenterologyUniversity of California, Irvine, Chief, Gastroenterology Section (111G), DVA Medical CenterLong BeachUSA

Personalised recommendations