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Down-regulation of P-cadherin with PF-03732010 inhibits cell migration and tumor growth in gastric cancer

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Summary

P-cadherin is frequently up-regulated in solid tumors such as gastric, colon, lung, pancreatic and breast cancers. Although P-cadherin promotes cadherin-mediated cell adhesion, the gastric cancer-linked regulation of P-cadherin has not been extensively investigated. In this study, we found epigenetic regulation of P-cadherin in human gastric cancer cells that was induced by treatment with DNA demethylating drug and histone deacetylase inhibitor. Silencing P-cadherin by using siRNA induces apoptosis in gastric cells and blocks expression of Tie-2, an angiogenic receptor tyrosine kinase. In contrast, ectopically expressed P-cadherin by generating P-cadherin stable cell line enhances Tie-2 expression and cell mobility. We also demonstrated that inhibition of P-cadherin by PF-03732010, a fully humanized anti-P-cadherin IgG1 monoclonal antibody, suppressed cell migration in vitro and tumor growth in BALB/c nude mice bearing SNU620 gastric cancer xenograft. The data reported here are the first to reveal that the inhibition of P-cadherin decreases tumor cell migration and blocks a tumorigenesis by down-regulation of Tie-2 in gastric cancer. This demonstrates the potential for P-cadherin to be used as a target for treatment of gastric cancer.

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Acknowledgements

This study was partly supported by a grant (A080316) of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea.

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The authors declare no conflict of interest.

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Correspondence to Do-Youn Oh.

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Park, J., Park, E., Han, SW. et al. Down-regulation of P-cadherin with PF-03732010 inhibits cell migration and tumor growth in gastric cancer. Invest New Drugs 30, 1404–1412 (2012). https://doi.org/10.1007/s10637-011-9710-9

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  • DOI: https://doi.org/10.1007/s10637-011-9710-9

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