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PMID: 12359056 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Ras farnesylation inhibitor FTI-277 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis.

Japanese journal of cancer research : Gann ·Vol. 93 ·No. 9 ·2002-09-00 ·Pages 1020-8

Nam JS, Ino Y, Sakamoto M, Hirohashi S

Abstract

The E-cadherin/catenin cell adhesion system is often down-regulated in epithelial tumors. This is thought to play an important role in cancer invasion and metastasis, and restoration of this system may suppress metastatic spread of cancer. In this study, the effects of a Ras farnesylation inhibitor (FTI-277) on E-cadherin-mediated cell-cell adhesion and metastatic potential were examined. In cell aggregation assays, FTI-277 stimulated aggregation of colon, liver and breast cancer cells. In vitro cultures of cancer cells showed that FTI-277 induced strong cell-cell contact. Immunoblotting analysis showed that FTI-277 increased E-cadherin/catenin (alpha, beta and gamma) expression and strongly stabilized E-cadherin/catenin with the actin cytoskeleton. Northern blotting studies indicated that the observed increase in the E-cadherin/catenin protein content was due to increased expression of their genes. After inoculation of the spleens of mice with severe combined immunodeficiency (SCID) with cancer cells, FTI-277 treatment for 3 weeks markedly reduced splenic primary tumor growth and the rate of liver metastasis compared with control counterparts. Our data demonstrate that FTI-277 can activate functioning of the E-cadherin-mediated cell adhesion system, which is associated with suppression of cancer cell metastasis. Therefore, selective inhibition of Ras activation may be useful for preventing cancer metastasis.

MeSH Terms
Cadherins/analysis,genetics Cell Aggregation/drug effects Cell Division/drug effects Cytoskeletal Proteins/analysis,genetics Desmoplakins Enzyme Inhibitors/pharmacology Genes, ras/drug effects,physiology Humans Methionine/analogs & derivatives,pharmacology Neoplasm Metastasis/prevention & control RNA, Messenger/analysis Trans-Activators/analysis,genetics Tumor Cells, Cultured alpha Catenin beta Catenin
Chemicals
CTNNA1 protein, human CTNNB1 protein, human Cadherins Cytoskeletal Proteins Desmoplakins Enzyme Inhibitors FTI 277 RNA, Messenger Trans-Activators alpha Catenin beta Catenin Methionine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Nam Jeong-Seok
Pathology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. shirohas@ncc.go.jp
Ino Yoshinori
Sakamoto Michiie
Hirohashi Setsuo
References (37)
37 references, click to expand
  1. H-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes.
    J Cell Biol. 1999 Sep 6;146(5):967-80 PMID: 10477752
  2. Src family kinase inhibitor PP2 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis.
    Clin Cancer Res. 2002 Jul;8(7):2430-6 PMID: 12114449
  3. Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines.
    Cancer Res. 2001 Apr 15;61(8):3508-17 PMID: 11309315
  4. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras.
    Cell. 1997 May 2;89(3):457-67 PMID: 9150145
  5. An inducible melanoma model implicates a role for RAS in tumor maintenance and angiogenesis.
    Cancer Metastasis Rev. 2000;19(1-2):121-9 PMID: 11191050
  6. Tumor growth and metastasis of human colorectal cancer cell lines in SCID mice resemble clinical metastatic behaviors.
    Invasion Metastasis. 1997;17(5):259-69 PMID: 9876220
  7. All ras proteins are polyisoprenylated but only some are palmitoylated.
    Cell. 1989 Jun 30;57(7):1167-77 PMID: 2661017
  8. Genomic sequencing.
    Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991-5 PMID: 6326095
  9. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers.
    Am J Pathol. 1998 Aug;153(2):333-9 PMID: 9708792
  10. Cloning of the human alpha-catenin cDNA and its aberrant mRNA in a human cancer cell line.
    Biochem Biophys Res Commun. 1993 Jun 30;193(3):897-904 PMID: 8323564
  11. Regulation of E-cadherin gene expression during tumor progression: the role of a new Ets-binding site and the E-pal element.
    Exp Cell Res. 1999 May 1;248(2):358-71 PMID: 10222128
  12. Novel Ras antagonist blocks human melanoma growth.
    Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):14019-24 PMID: 10570191
  13. Cadherins in cancer: implications for invasion and metastasis.
    Curr Opin Cell Biol. 1993 Oct;5(5):806-11 PMID: 8240824
  14. Activation of both MAP kinase and phosphatidylinositide 3-kinase by Ras is required for hepatocyte growth factor/scatter factor-induced adherens junction disassembly.
    Mol Biol Cell. 1998 Aug;9(8):2185-200 PMID: 9693375
  15. Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas.
    Cancer Res. 1989 Apr 15;49(8):2128-33 PMID: 2702654
  16. Dominant inhibitory Ras mutants selectively inhibit the activity of either cellular or oncogenic Ras.
    Mol Cell Biol. 1991 Aug;11(8):4053-64 PMID: 2072908
  17. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly.
    J Cell Biol. 1994 Jun;125(6):1327-40 PMID: 8207061
  18. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity.
    Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6403-7 PMID: 1631135
  19. Restoration of tight junction structure and barrier function by down-regulation of the mitogen-activated protein kinase pathway in ras-transformed Madin-Darby canine kidney cells.
    Mol Biol Cell. 2000 Mar;11(3):849-62 PMID: 10712504
  20. E-cadherin is involved in the intrahepatic metastasis of hepatocellular carcinoma.
    Hepatology. 1996 Dec;24(6):1460-7 PMID: 8938181
  21. Ras-induced transformation and signaling pathway.
    J Biochem. 1999 Nov;126(5):799-803 PMID: 10544270
  22. Cadherin dysfunction in a human cancer cell line: possible involvement of loss of alpha-catenin expression in reduced cell-cell adhesiveness.
    Cancer Res. 1992 Oct 15;52(20):5770-4 PMID: 1394201
  23. A causal role for E-cadherin in the transition from adenoma to carcinoma.
    Nature. 1998 Mar 12;392(6672):190-3 PMID: 9515965
  24. p21ras is modified by a farnesyl isoprenoid.
    Proc Natl Acad Sci U S A. 1989 Nov;86(21):8323-7 PMID: 2682646
  25. Rho-stimulated contractility contributes to the fibroblastic phenotype of Ras-transformed epithelial cells.
    Mol Biol Cell. 1997 Nov;8(11):2329-44 PMID: 9362072
  26. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro.
    Cancer Res. 2001 Jan 1;61(1):131-7 PMID: 11196150
  27. Thymosin beta-4 expression is correlated with metastatic capacity of colorectal carcinomas.
    Biochem Biophys Res Commun. 1993 Jun 15;193(2):706-10 PMID: 8512568
  28. Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell-cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase.
    J Cell Biol. 1998 Nov 30;143(5):1385-98 PMID: 9832565
  29. Stimulation of membrane ruffling and MAP kinase activation by distinct effectors of RAS.
    Science. 1996 Feb 9;271(5250):810-2 PMID: 8628998
  30. Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
    Carcinogenesis. 2000 Jan;21(1):113-6 PMID: 10607742
  31. A new human pleomorphic hepatocellular carcinoma cell line, KYN-2.
    Acta Pathol Jpn. 1988 Aug;38(8):953-66 PMID: 2847482
  32. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.
    Nat Med. 1999 Jul;5(7):810-6 PMID: 10395327
  33. Dominant negative inhibition of the association between beta-catenin and c-erbB-2 by N-terminally deleted beta-catenin suppresses the invasion and metastasis of cancer cells.
    Oncogene. 1996 Sep 5;13(5):883-9 PMID: 8806677
  34. Possible involvement of the inactivation of the Rho-Rho-kinase pathway in oncogenic Ras-induced transformation.
    Oncogene. 1998 Dec 3;17(22):2863-71 PMID: 9879992
  35. c-erbB-2 gene product directly associates with beta-catenin and plakoglobin.
    Biochem Biophys Res Commun. 1995 Mar 28;208(3):1067-72 PMID: 7702605
  36. Multiple Ras functions can contribute to mammalian cell transformation.
    Cell. 1995 Feb 24;80(4):533-41 PMID: 7867061
  37. Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas.
    Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7416-9 PMID: 7543680
Article Info
Journal
Japanese journal of cancer research : Gann
Abbr.
Jpn J Cancer Res
ISSN
0910-5050
DOI
10.1111/j.1349-7006.2002.tb02479.x
Email
shirohas@ncc.go.jp
Published
2002-09-00
Pages
1020-8
Language
English
Region
Japan
NLM ID
8509412
PMCID
PMC5927130
Subset
IM
External Links
PubMed source DOI: 10.1111/j.1349-7006.2002.tb02479.x PMC Full Text
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