This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nam, J.-S. Articles by Hirohashi, S. Search for Related Content PubMed PubMed Citation Articles by Nam, J.-S. Articles by Hirohashi, S.

Src Family Kinase Inhibitor PP2 Restores the E-Cadherin/Catenin Cell Adhesion System in Human Cancer Cells and Reduces Cancer Metastasis¹

Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan

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.

This article has been cited by other articles:

				L. J. Inge, S. A. Rajasekaran, D. Wolle, S. P. Barwe, S. Ryazantsev, C. M. Ewing, W. B. Isaacs, and A. K. Rajasekaran {alpha}-Catenin overrides Src-dependent activation of {beta}-catenin oncogenic signaling Mol. Cancer Ther., June 1, 2008; 7(6): 1386 - 1397. [Abstract] [Full Text] [PDF]

				J.-S. Nam, M. Terabe, M.-J. Kang, H. Chae, N. Voong, Y.-a. Yang, A. Laurence, A. Michalowska, M. Mamura, S. Lonning, et al. Transforming Growth Factor {beta} Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin-17 Cancer Res., May 15, 2008; 68(10): 3915 - 3923. [Abstract] [Full Text] [PDF]

				A. Spreafico, S. Schenone, T. Serchi, M. Orlandini, A. Angelucci, D. Magrini, G. Bernardini, G. Collodel, A. Di Stefano, C. Tintori, et al. Antiproliferative and proapoptotic activities of new pyrazolo[3,4-d]pyrimidine derivative Src kinase inhibitors in human osteosarcoma cells FASEB J, May 1, 2008; 22(5): 1560 - 1571. [Abstract] [Full Text] [PDF]

				F.-P. Liang, C.-H. Lin, C.-D. Kuo, H.-P. Chao, and S.-L. Fu Suppression of v-Src Transformation by Andrographolide via Degradation of the v-Src Protein and Attenuation of the Erk Signaling Pathway J. Biol. Chem., February 22, 2008; 283(8): 5023 - 5033. [Abstract] [Full Text] [PDF]

				K. Fizazi The role of Src in prostate cancer Ann. Onc., November 1, 2007; 18(11): 1765 - 1773. [Abstract] [Full Text] [PDF]

				M. Dimri, M. Naramura, L. Duan, J. Chen, C. Ortega-Cava, G. Chen, R. Goswami, N. Fernandes, Q. Gao, G. P. Dimri, et al. Modeling Breast Cancer-Associated c-Src and EGFR Overexpression in Human MECs: c-Src and EGFR Cooperatively Promote Aberrant Three-dimensional Acinar Structure and Invasive Behavior Cancer Res., May 1, 2007; 67(9): 4164 - 4172. [Abstract] [Full Text] [PDF]

				A. Serrels, I. R.J. Macpherson, T.R. J. Evans, F. Y. Lee, E. A. Clark, O. J. Sansom, G. H. Ashton, M. C. Frame, and V. G. Brunton Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib Mol. Cancer Ther., December 1, 2006; 5(12): 3014 - 3022. [Abstract] [Full Text] [PDF]

				J.-S. Nam, M.-J. Kang, A. M. Suchar, T. Shimamura, E. A. Kohn, A. M. Michalowska, V. C. Jordan, S. Hirohashi, and L. M. Wakefield Chemokine (C-C motif) ligand 2 mediates the prometastatic effect of dysadherin in human breast cancer cells. Cancer Res., July 15, 2006; 66(14): 7176 - 7184. [Abstract] [Full Text] [PDF]

				J.-S. Nam, A. M. Suchar, M.-J. Kang, C. H. Stuelten, B. Tang, A. M. Michalowska, L. W. Fisher, N. S. Fedarko, A. Jain, J. Pinkas, et al. Bone Sialoprotein Mediates the Tumor Cell-Targeted Prometastatic Activity of Transforming Growth Factor {beta} in a Mouse Model of Breast Cancer. Cancer Res., June 15, 2006; 66(12): 6327 - 6335. [Abstract] [Full Text] [PDF]

				H.-X. Yan, W. Yang, R. Zhang, L. Chen, L. Tang, B. Zhai, S.-Q. Liu, H.-F. Cao, X.-B. Man, H.-P. Wu, et al. Protein-tyrosine Phosphatase PCP-2 Inhibits beta-Catenin Signaling and Increases E-cadherin-dependent Cell Adhesion J. Biol. Chem., June 2, 2006; 281(22): 15423 - 15433. [Abstract] [Full Text] [PDF]

				J. G. Trevino, J. M. Summy, D. P. Lesslie, N. U. Parikh, D. S. Hong, F. Y. Lee, N. J. Donato, J. L. Abbruzzese, C. H. Baker, and G. E. Gallick Inhibition of Src Expression and Activity Inhibits Tumor Progression and Metastasis of Human Pancreatic Adenocarcinoma Cells in an Orthotopic Nude Mouse Model Am. J. Pathol., March 1, 2006; 168(3): 962 - 972. [Abstract] [Full Text] [PDF]

				C. E. Pullar and R. R. Isseroff The {beta}2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms J. Cell Sci., February 1, 2006; 119(3): 592 - 602. [Abstract] [Full Text] [PDF]

				J. M. Golas, J. Lucas, C. Etienne, J. Golas, C. Discafani, L. Sridharan, E. Boghaert, K. Arndt, F. Ye, D. H. Boschelli, et al. SKI-606, a Src/Abl Inhibitor with In vivo Activity in Colon Tumor Xenograft Models Cancer Res., June 15, 2005; 65(12): 5358 - 5364. [Abstract] [Full Text] [PDF]

				V. G. Brunton, E. Avizienyte, V. J. Fincham, B. Serrels, C. A. Metcalf III, T. K. Sawyer, and M. C. Frame Identification of Src-Specific Phosphorylation Site on Focal Adhesion Kinase: Dissection of the Role of Src SH2 and Catalytic Functions and Their Consequences for Tumor Cell Behavior Cancer Res., February 15, 2005; 65(4): 1335 - 1342. [Abstract] [Full Text] [PDF]

				F. Palacios, J. S. Tushir, Y. Fujita, and C. D'Souza-Schorey Lysosomal Targeting of E-Cadherin: a Unique Mechanism for the Down-Regulation of Cell-Cell Adhesion during Epithelial to Mesenchymal Transitions Mol. Cell. Biol., January 1, 2005; 25(1): 389 - 402. [Abstract] [Full Text] [PDF]

				M. F. McCarty Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy Integr Cancer Ther, December 1, 2004; 3(4): 349 - 380. [Abstract] [PDF]

				S. Weis, J. Cui, L. Barnes, and D. Cheresh Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis J. Cell Biol., October 25, 2004; 167(2): 223 - 229. [Abstract] [Full Text] [PDF]

				M. S. Duxbury, H. Ito, M. J. Zinner, S. W. Ashley, and E. E. Whang Inhibition of Src Tyrosine Kinase Impairs Inherent and Acquired Gemcitabine Resistance in Human Pancreatic Adenocarcinoma Cells Clin. Cancer Res., April 1, 2004; 10(7): 2307 - 2318. [Abstract] [Full Text] [PDF]

				D. M. Weinreich, D. M. Elaraj, M. Puhlmann, S. M. Hewitt, N. M. Carroll, E. D. Feldman, E. M. Turner, P. J. Spiess, and H. R. Alexander Effect of Interleukin 1 Receptor Antagonist Gene Transduction on Human Melanoma Xenografts in Nude Mice Cancer Res., September 15, 2003; 63(18): 5957 - 5961. [Abstract] [Full Text] [PDF]