Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity |
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Authors: | Guven Yenmis Elif Yaprak Sarac Nail Besli Tugba Soydas Cihan Tastan Derya Dilek Kancagi Muhammet Yilanci Kazim Senol Onur Olgac Karagulle Cumhur Gokhan Ekmekci Ercument Ovali Matem Tuncdemir Turgut Ulutin Gonul Kanigur Sultuybek |
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Institution: | 1. Biruni University, Faculty of Medicine, Department of Medical Biology, Istanbul, Turkey;2. Istanbul Technical University, Faculty of Science and Letters, Department of Molecular Biology-Genetics and Biotechnology, Istanbul, Turkey;3. University of Saglik Bilimleri, Faculty of Medicine, Department of Medical Biology, Istanbul, Turkey;4. Istanbul Aydin University, Faculty of Medicine, Department of Medical Biology and Genetics, Istanbul, Turkey;5. Uskudar University, Faculty of Engineering and Natural Sciences, Department of Molecular Biology and Genetics, Istanbul, Turkey;6. Acibadem Labcell Cell Laboratory, Istanbul, Turkey;7. Uludag University, Faculty of Medicine, Department of Breast Surgery, Bursa, Turkey;8. Mimar Sinan State Hospital, Department of General Surgery, Istanbul, Turkey;9. Acibadem Healthcare Group, Acibadem Labgen Genetic Diagnostic Center, Istanbul, Turkey;10. Istanbul University-Cerrahpasa, Faculty of Medicine, Department of Medical Biology, Istanbul, Turkey |
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Abstract: | Current evidence strongly suggests that aberrant activation of the nuclear factor kappa B (NF-kB) signaling cascade is connected to carcinogenesis. The matrix metalloproteinases (MMP) which are also the key agents for tumor metastasis may be potent candidates for tumor diagnosis in clinics. In this in vitro study, we hypothesized that metformin with an effective dose can inhibit tumor cell proliferation and metastasis by modulating the expressions of MMP-2 and -9 and interfering with NF-kB signaling in primary breast cancer cells (PBCCs). 300 000 cells per ml were obtained from biopsies of breast tumors from five human donors. The cell viability and proliferation were tested. Immunocytochemistry was performed for MMP-2, MMP-9, and NF-kB, and enzyme-linked immunosorbent assay for NF-kB activity, quantitative real-time PCR for RELA/p65, IkBα, MMP-2, and MMP-9. Three different doses of metformin (5, 10, and 25 mM) (Met) reduced the viability and proliferation of PBCCs in a dose-dependent manner, maximum inhibition was observed at 25 mM Met. The expression of RELA/p65 was not affected by 25 mM Met. Nuclear immunoreactivity and activity of NF-kB reduced while cytoplasmic NF-kB (p65) elevated by 25 mM Met compared to non-treatment (P < 0.05). The expression and immunoreactivity of MMP-9 but not MMP-2 were decreased by 25 mM Met treatment, compared with the non-treatment (P < 0.05). Metformin may have an essential antitumor role in the invasion and metastasis pathways of PBCCs by downregulating the MMP-9 expression blocking both the activity and nuclear translocation of NF-kB. |
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Keywords: | NF-kB Metformin Breast cancer MMP-2 MMP-9 |
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