Ras Farnesylation Inhibitor FTI‐277 Restores the E‐Cadherin/Catenin Cell Adhesion System in Human Cancer Cells and Reduces Cancer Metastasis

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 (α α α α, β β β β and γ γ γ γ) 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. Key words: E-Cadherin -Catenin -Ras -FTI-277 -MetastasisCadherin-mediated cell-cell adhesion plays a critical role in the establishment and maintenance of cell polarity and cell society. The transmembrane glycoprotein E-cadherin represents the predominant cadherin in epithelial cells and is responsible for cell-cell contact by complexing with the actin cytoskeleton via three major cytoplasmic catenins (α-, β-and γ-catenin). Alterations in the expression or function of the E-cadherin/catenin cell adhesion system occur frequently in a wide variety of human carcinomas.1, 2) Indeed, a causal role for the loss of E-cadherin during the transition from adenoma to invasive carcinoma has recently been demonstrated.3) However, the molecular mechanisms underlying the loss of expression or functionality of individual components of the Ecadherin/catenin complex in tumorigenesis are still poorly understood.Ras is a signal-transducing, guanine nucleotide-binding protein for various membrane receptors and it participates in the regulation of cell proliferation, differentiation and morphology. Activated Ras oncogenes have been identified in various forms of human cancer, 4) and several lines of evidence suggest that activation of Ras induces dysfunction of the E-cadherin system. For example, microinjection of Ras oncogenes into Madin-Darby canine kidney (MDCK) cells induced adherens junction disassembly.5) In addition, introduction of the Ras oncogene into keratinocytes promoted loss of E-cadherin and α-catenin and relocalization of β-catenin to the cytoplasm and nucleus. 6)A recent study demonstrated that down-regul...

Csk defines the ability of integrin-mediated cell adhesion and migration in human colon cancer cells: implication for a potential role in cancer metastasis

“…When the aggregated HCT15 cells expressing Csk K þ were subsequently infected with virus carrying Csk KÀ, the cells became scattered again, demonstrating that the morphological changes can be regulated reversibly (D). As reported previously (Nam et al, 2002), treatment with PP2, a specific inhibitor of SFK, induces cell aggregation in both cell types (E and J). Cell aggregation could also be induced by the PP2 treatment in HT29 cells expressing Csk KÀ (I).…”

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells

“…We and others have recently identified a role for Src kinase in acquired endocrine resistance in vitro [11,19], where it may regulate both proliferative and invasive responses in such cells. Data is emerging which reveals Src kinase as a novel tumour target, where its inhibition is effective at suppressing proliferation and/or metastatic events in a wide range of tumour types including CML [30,31], colon tumours [32,33] and pancreatic cancer [34,35]. Further studies [36,37] also provide compelling evidence that targeting Src may be of value in combination with existing chemotherapy to provide an augmented antitumour response.…”

Src family kinase members have a common response to histone deacetylase inhibitors in human colon cancer cells

“…Secondly, it is well accepted that inhibition of either individual SFKs by targeted approaches (e.g., antisense) or all SFKs generally by pharmacologic agents can markedly affect proliferation, tumorigenicity and survival of various tumor cell types. 13,56,57 Since HDIs appear to co-coordinately repress expression of multiple SFKs, this could help explain the wide variety of cancer cell types affected by this promising class of new anticancer drugs. However, at this point, it is unclear if the downregulation of SFKs by HDIs described here plays a direct role in the growth arrest and death of cancer cells in culture and whether HDI-mediated regulation of SFKs inhibits tumorigenicity or metastasis in vivo.…”