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Inhibition of matrix metalloproteinase-9 expression by docosahexaenoic acid mediated by heme oxygenase 1 in 12-O-tetradecanoylphorbol-13-acetate-induced MCF-7 human breast cancer cells

  • Molecular Toxicology
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Abstract

Matrix metalloproteinase-9 (MMP-9) plays a crucial role in tumor metastasis. Previous studies showed that polyunsaturated fatty acids exhibit an anti-cancer effect in various human carcinoma cells, but the effect of docosahexaenoic acid (DHA) and linoleic acid (LA) on metastasis of breast cancer cells is not fully clarified. We studied the anti-metastasis potential of DHA and LA in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MCF-7 cells. We found that TPA (100 ng/ml) induced MMP-9 enzyme activity both dose- and time-dependently, and 200 μM DHA and LA significantly inhibited MMP-9 mRNA and protein expression, enzyme activity, cell migration, and invasion. Treatment with PD98059 (10 μM), wortmannin (10 μM), and GF109203X (0.5 μM) decreased TPA-induced MMP-9 protein expression and enzyme activity. TPA-induced activation of ERK1, Akt, and PKCδ was attenuated by DHA, whereas LA attenuated only ERK1 activation. GF109203X also suppressed ERK1 activation. EMSA showed that DHA, LA, PD98059, and wortmannin decreased TPA-induced NF-κB and AP-1 DNA-binding activity. Furthermore, DHA rather than LA dose-dependently increased HO-1 expression. HO-1 siRNA alleviated the inhibition by DHA of TPA-induced MMP-9 protein expression and enzyme activity in MCF-7 cells, and HO-1 knockdown reversed the DHA inhibition of cell migration. These results suggest that DHA and LA have both similar and divergent signaling pathways in the suppression of TPA-induced MCF-7 metastasis.

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Acknowledgments

This study was supported by grant CMU100-ASIA-09.

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The authors have declared no conflict of interest.

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Authors and Affiliations

  1. Department of Nutrition, China Medical University, Taichung, Taiwan, ROC

    Haw-Wen Chen, Li-Lin Lin & Chong-Kuei Lii

  2. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, ROC

    Che-Yi Chao

  3. School of Nutrition, Chung Shan Medical University, Taichung, Taiwan, ROC

    Chia-Yang Lu, Kai-Li Liu & Chien-Chun Li

  4. Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC

    Chia-Yang Lu, Kai-Li Liu & Chien-Chun Li

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  1. Haw-Wen Chen
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  2. Che-Yi Chao
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Chen, HW., Chao, CY., Lin, LL. et al. Inhibition of matrix metalloproteinase-9 expression by docosahexaenoic acid mediated by heme oxygenase 1 in 12-O-tetradecanoylphorbol-13-acetate-induced MCF-7 human breast cancer cells. Arch Toxicol 87, 857–869 (2013). https://doi.org/10.1007/s00204-012-1003-3

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