Top

Published in:

01-01-2007 | Original Paper

Rebamipide Inhibits Gastric Cancer Cell Growth

Authors: Tetsuya Tanigawa, Rama Pai, Tetsuo Arakawa, Andrzej S. Tarnawski

Published in: Digestive Diseases and Sciences | Issue 1/2007

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.

Parkin DM, Pisani P, Ferlay J (1993) Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer 54:594–606CrossRefPubMed

Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr (1991) Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265:1287–1289CrossRefPubMed

Howson CP, Hiyama T, Wynder EL (1986) The decline in gastric cancer; epidemiology of an unplanned triumph. Epidemiol Rev 8:1–27PubMed

Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process-First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52:6735–6740PubMed

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 112–126

Sherr CJ (2000) The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 60:3689–3695PubMed

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 92:5545–5549CrossRefPubMed

Hannon GJ, Beach D (1994) p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 371:257–261, 1994CrossRefPubMed

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 8:9–22CrossRefPubMed

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 9:1831–1845CrossRefPubMed

11.

Attisano L, Wrana JL (2002) Signal transduction by the TGF-β superfamily. Science 296:1646–1647CrossRefPubMed

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 274:8797–8805CrossRefPubMed

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 12:1587–1592PubMed

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 17:1576–1578PubMed

15.

Hayes SA, Huang X, Kambhampati S, Platanias LC, Bergan RC (2003) MAP kinase modulates Smad-dependent changes in human prostate cell adhesion. Oncogene 22:4841–4850CrossRefPubMed

16.

Heldin CH, Miyazono K, ten Dijke P (1997) TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471CrossRefPubMed

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 95:6733–6738CrossRefPubMed

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 275:29244–29256CrossRefPubMed

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 9:3309–3319PubMed

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–13SPubMed

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 40:2469–2472

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 212:219–213CrossRef

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–98SPubMed

24.

Kleine A, Kluge S, Peskar BM (1993) Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of Rebamipide in rats. Dig Dis Sci 38:1441–1449CrossRefPubMed

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 42:319–325CrossRefPubMed

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 18:117–123CrossRefPubMed

27.

Sakurai K, Yamasaki K (1994) Protective effect of Rebamipide against hydrogen peroxide-induced hemorrhagic mucosal lesions in rat stomach. Jpn J Pharmacol 64:229–234PubMed

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 41:1139–1144CrossRefPubMed

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–211SPubMed

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 334:207–212

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 56:364–369PubMedCrossRef

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 8:289–293CrossRefPubMed

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 50:1–7PubMed

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 39:603–610CrossRefPubMed

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 94:2107–2112CrossRefPubMed

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 7:479–483PubMed

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 129:463–471CrossRefPubMed

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 8:23–35CrossRefPubMed

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 289:350–357CrossRefPubMed

40.

Kretzschmar M, Doody J, Timokhina I, Massague J (1999) A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev 13:804–816PubMed

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 274:33637–33643CrossRefPubMed

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 276:33986–33994CrossRefPubMed

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 276:14466–14473PubMed

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 47:1399–1404CrossRefPubMed

Title: Rebamipide Inhibits Gastric Cancer Cell Growth
Authors: Tetsuya Tanigawa
Rama Pai
Tetsuo Arakawa
Andrzej S. Tarnawski
Publication date: 01-01-2007
Publisher: Springer US
Published in: Digestive Diseases and Sciences / Issue 1/2007
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-006-9226-x

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Rebamipide Inhibits Gastric Cancer Cell Growth

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2007

Primary Coloduodenal Fistula in a Patient with Crohn's Disease

Acute Variceal Bleed in a Patient with Idiopathic Myelofibrosis Successfully Treated with Endoscopic Variceal Band Ligation

Effect of Nitric Oxide on Histamine-Induced Cytological Transformations in Parietal Cells in Isolated Human Gastric Glands

Acute Hemorrhage Following Transhepatic PEG Tube Placement

Human Pancreatic Digestive Enzymes

Anti-Saccharomyces cerevisiae Antibody Does Not Differentiate Between Crohn's Disease and Intestinal Tuberculosis

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page