Src family kinase inhibitor PP2 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis.
The E-cadherin/catenin cell adhesion system is often down-regulatedin epithelial tumors. This is thought to play an important role in cancer invasion and metastasis. Restoring this system may enable suppression of the metastatic spread of cancer. This study examined the effect of Src family kinase inhibitor PP2 on E-cadherin-mediated cell-cell adhesion and metastatic potentials. In cell aggregation assays, PP2 stimulated the aggregation of colon, liver, and breast cancer cells. In vitro cultures of cancer cells showed that PP2 induced strong cell-cell contact. Immunoblot analysis showed that PP2 enhanced E-cadherin/catenin expression and that increased E-cadherin/catenin proteins were strongly associated with the actin cytoskeleton. Northern blot studies indicated that the observed increase of E-cadherin/catenin protein content was due to their increased gene expression. After the spleens of severe combined immunodeficient mice were inoculated with cancer cells, treatment with PP2 for 3 weeks markedly reduced the rate of liver metastasis, compared with the control counterparts. Our data demonstrate that PP2 can activate the functioning of the E-cadherin-mediated cell adhesion system, which is associated with the suppression of metastasis in cancer cells. Thus, selective inhibition of Src activation may be potentially useful in the prevention of cancer metastasis.
Nam
Jeong-Seok
JS
Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Ino
Yoshinori
Y
Sakamoto
Michiie
M
Hirohashi
Setsuo
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015820:Cadherins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013160:Splenic Neoplasms / Q000473:pathology / Q000517:prevention & control; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C412373:AG 1879; D000970:Antineoplastic Agents; D015820:Cadherins; D003598:Cytoskeletal Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; D019061:src-Family Kinases; D002118:Calcium