Valproic acid modulates radiation-enhanced matrix metalloproteinase activity and invasion of breast cancer cells

Abstract

Purpose: To evaluate matrix metalloproteinase (MMP) activity and invasion after ionizing radiation (IR) exposure and to determine whether MMP could be epigenetically modulated by histone deacetylase (HDAC) inhibition.

Material and methods: Two human breast cancer cell lines (MDA-MB-231 and MCF-7) were cultured in monolayer (2D) and in laminin-rich extracellular matrix (3D). Invasion capability, collagenolytic and gelatinolytic activity, MMP and TIMP protein and mRNA expression and clonogenic survival were analyzed after IR exposure, with and without a HDAC inhibition treatment [1.5 mM valproic acid (VA) or 1 μM trichostatin-A (TSA)].

Results: IR exposure resulted in cell line-dependent stimulation of invasion capacity. In contrast to MCF-7 cells, irradiated MDA-MB-231 showed significantly enhanced mRNA expression of mmp-1, mmp-3 and mmp-13 and of their regulators timp-1 and timp-2 relative to unirradiated controls. This translated into increased collagenolytic and gelatinolytic activity and could be reduced after valproic acid (VA) treatment. Additionally, VA also mitigated IR-enhanced mmp and timp mRNA expression as well as IR-increased invasion capability. Finally, our data confirm the radiosensitizing effect of VA.

Conclusion: These results suggest that IR cell line-dependently induces upregulation of MMP mRNA expression, which appears to be mechanistically linked to a higher invasion capability that is modifiable by HDAC inhibition.

Keywords:

• Matrix metalloproteinases
• ionizing radiation
• breast cancer
• tumour microenvironment
• histone deacetylases
• invasion
• epigenetic regulation

Acknowledgements

The authors thank Richard Davies for improving the English style of the manuscript.

Declaration of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Funding

This study was supported by the Fondo de Investigación Sanitaria (PI080728) and the Andalusian Council of Health (PI0730-2013) to M. I. Núñez. A grant from the Spanish Ministry of Science and Education to F. Artacho-Cordón (FPU12/02524) greatly aided this work. S. Ríos-Arrabal is supported by the Fundación Benéfica San Francisco Javier y Santa Cándida, University of Granada. This research was also funded by the San Cecilio University Hospital, Granada. Nils Cordes received grants from the Bundesministerium für Bildung und Forschung (BMBF Contract 03ZIK041 to N.C.) and the Saxon Ministry of Science and Arts and the EFRE Europäische Fonds für regionale Entwicklung, Europa fördert Sachsen (100066308).

Supplementary material available online Supplementary Table 1 and Figures 1-9 are available via the supplementary tab online at http://dx.doi.org/10.3109/09553002.2015.1087067