Ras Farnesylation Inhibitor FTI-277 Restores the E-cadherin/catenin Cell Adhesion System in Human Cancer Cells and Reduces Cancer Metastasis

Overview

Journal Jpn J Cancer Res

Specialty Oncology

Date 2002 Oct 3

PMID 12359056

Citations 11

Authors

Jeong-Seok Nam

Yoshinori Ino

Michiie Sakamoto

Setsuo Hirohashi

Affiliations

Soon will be listed here.

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.

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References

Espada J, Perez-Moreno M, BRAGA V, Rodriguez-Viciana P, Cano A . H-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes. J Cell Biol. 1999; 146(5):967-80. PMC: 2169475. DOI: 10.1083/jcb.146.5.967. View

Nam J, Ino Y, Sakamoto M, Hirohashi S . 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; 8(7):2430-6. View

Menke A, Philippi C, Vogelmann R, Seidel B, Lutz M, Adler G . Down-regulation of E-cadherin gene expression by collagen type I and type III in pancreatic cancer cell lines. Cancer Res. 2001; 61(8):3508-17. View

Rodriguez-Viciana P, Warne P, Khwaja A, Marte B, Pappin D, Das P . Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell. 1997; 89(3):457-67. DOI: 10.1016/s0092-8674(00)80226-3. View

Wong A, Chin L . An inducible melanoma model implicates a role for RAS in tumor maintenance and angiogenesis. Cancer Metastasis Rev. 2001; 19(1-2):121-9. DOI: 10.1023/a:1026537423753. View

Yasui N, Sakamoto M, Ochiai A, Ino Y, Akimoto S, Orikasa A . Tumor growth and metastasis of human colorectal cancer cell lines in SCID mice resemble clinical metastatic behaviors. Invasion Metastasis. 1997; 17(5):259-69. View

Hancock J, Magee A, Childs J, Marshall C . All ras proteins are polyisoprenylated but only some are palmitoylated. Cell. 1989; 57(7):1167-77. DOI: 10.1016/0092-8674(89)90054-8. View

Church G, Gilbert W . Genomic sequencing. Proc Natl Acad Sci U S A. 1984; 81(7):1991-5. PMC: 345422. DOI: 10.1073/pnas.81.7.1991. View

Hirohashi S . Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol. 1998; 153(2):333-9. PMC: 1852964. DOI: 10.1016/S0002-9440(10)65575-7. View

10.

Oda T, Kanai Y, Shimoyama Y, Nagafuchi A, Tsukita S, Hirohashi S . Cloning of the human alpha-catenin cDNA and its aberrant mRNA in a human cancer cell line. Biochem Biophys Res Commun. 1993; 193(3):897-904. DOI: 10.1006/bbrc.1993.1710. View

11.

Rodrigo I, Cato A, Cano A . 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; 248(2):358-71. DOI: 10.1006/excr.1999.4438. View

12.

Jansen B, Kahr H, Heere-Ress E, Mayer B, Eichler H, Pehamberger H . Novel Ras antagonist blocks human melanoma growth. Proc Natl Acad Sci U S A. 1999; 96(24):14019-24. PMC: 24183. DOI: 10.1073/pnas.96.24.14019. View

13.

Takeichi M . Cadherins in cancer: implications for invasion and metastasis. Curr Opin Cell Biol. 1993; 5(5):806-11. DOI: 10.1016/0955-0674(93)90029-p. View

14.

Potempa S, Ridley A . 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; 9(8):2185-200. PMC: 25472. DOI: 10.1091/mbc.9.8.2185. View

15.

Shimoyama Y, Hirohashi S, Hirano S, Noguchi M, Shimosato Y, Takeichi M . Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas. Cancer Res. 1989; 49(8):2128-33. View

16.

Stacey D, Feig L, Gibbs J . Dominant inhibitory Ras mutants selectively inhibit the activity of either cellular or oncogenic Ras. Mol Cell Biol. 1991; 11(8):4053-64. PMC: 361212. DOI: 10.1128/mcb.11.8.4053-4064.1991. View

17.

Hinck L, Nathke I, Papkoff J, Nelson W . Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J Cell Biol. 1994; 125(6):1327-40. PMC: 2290923. DOI: 10.1083/jcb.125.6.1327. View

18.

Kato K, Cox A, Hisaka M, Graham S, Buss J, Der C . Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci U S A. 1992; 89(14):6403-7. PMC: 49509. DOI: 10.1073/pnas.89.14.6403. View

19.

Chen Y, Lu Q, Schneeberger E, Goodenough D . 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; 11(3):849-62. PMC: 14815. DOI: 10.1091/mbc.11.3.849. View

20.

Osada T, Sakamoto M, Ino Y, Iwamatsu A, Matsuno Y, Muto T . E-cadherin is involved in the intrahepatic metastasis of hepatocellular carcinoma. Hepatology. 1996; 24(6):1460-7. DOI: 10.1053/jhep.1996.v24.pm0008938181. View