Valproic acid modulates radiation-enhanced matrix metalloproteinase activity and invasion of breast cancer cells.
Valproic acid modulates radiation-enhanced matrix metalloproteinase activity and invasion of breast cancer cells.
Artacho-Cordón, F.; Ríos-Arrabal, S.; Olivares-Urbano, M. A.; Storch, K.; Dickreuter, E.; Muñoz-Gámez, J. A.; León, J.; Calvente, I.; Torné, P.; Salinas, M. D.; Cordes, N.; Núñez, M. I.
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; breast cancer; epigenetic regulation; histone deacetylases; invasion; ionizing radiation; tumour microenvironment
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International Journal of Radiation Biology 91(2015)12, 946-956
Online First (2015) DOI: 10.3109/09553002.2015.1087067
Cited 10 times in Scopus
Permalink: https://www.hzdr.de/publications/Publ-22847