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Impairment of breast cancer cell invasion by COX-2-specific inhibitor NS398: roles of CXCR4 and of uPA system

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Abstract

Inhibition of cyclooxygenase-2 (COX-2) is known to impair cancer cell metastatic behaviour, but the mechanisms involved largely remain elusive. We aimed to analyse whether the antimetastatic effect of COX-2 inhibition in breast cancer cells could be explained by variations in the expression levels of chemokine receptor CXCR4, vascular endothelium growth factor (VEGF) and UPA/UPAR components of the urokinase plasminogen activator system (uPAR). Breast cancer cell line MDA-MB-231 was exposed to COX-2-specific inhibitor NS398. Experimental data were assessed using Matrigel invasion tests, qRT-PCR, ELISA, flow cytometry and MTT test. Exposure to NS398 had no major effect on cell viability, apoptosis or VEGF production. Cell invasion was significantly decreased with reductions ranging from of 3.6% with 10 μM NS398 to 81.04% with 100 μM NS398. CXCR4 membrane expression was significantly reduced by 18% (P < 0.05) when cells were treated with 100 μM of NS398 for 72 h. UPA mRNA levels were significantly reduced to 78 and 63% after treatment with 10 μM NS398 for 48 and 72 h, respectively (P < 0.05). UPAR mRNA levels also decreased with mild NS398 concentrations, reaching the lowest level of 56% with 50 μM of NS398 for 48 h (P < 0.05). With NS398 higher concentrations, UPAR and UPA expression levels increased. According to our results, impairment of expression of CXCR4, UPA and UPAR differentially contribute to the antimetastatic effect of COX-2 inhibitors depending on drug concentration.

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Acknowledgments

We are grateful to Professor Carlos de Oliveira from CIMAGO and to Fundação Calouste Gulbenkian for funding this work.

Conflict of interest

All authors state there is no conflict of interest evolving this paper.

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Authors and Affiliations

  1. Department of Medical Genetics and CIMAGO, Faculty of Medicine, University of Coimbra, Pólo III, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal

    Henriqueta Coimbra Silva, Luis Alcides Mesquita Nogueira & Fernando Regateiro

  2. Central Laboratory of Cytometry and CIMAGO, Faculty of Medicine, University of Coimbra, Pólo I, Rua Larga, 3004-504, Coimbra, Portugal

    Vera Alves & Manuel Santos Rosa

  3. Department of Pathology and CIMAGO, Faculty of Medicine, University of Coimbra, Pólo I, Rua Larga, 3004-504, Coimbra, Portugal

    Lina Carvalho

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  1. Henriqueta Coimbra Silva
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  2. Vera Alves
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  3. Luis Alcides Mesquita Nogueira
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Correspondence to Henriqueta Coimbra Silva.

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Silva, H.C., Alves, V., Nogueira, L.A.M. et al. Impairment of breast cancer cell invasion by COX-2-specific inhibitor NS398: roles of CXCR4 and of uPA system. Med Oncol 29, 1468–1476 (2012). https://doi.org/10.1007/s12032-011-9995-8

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  • DOI: https://doi.org/10.1007/s12032-011-9995-8

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