Gemifloxacin inhibits migration and invasion and induces mesenchymal–epithelial transition in human breast adenocarcinoma cells
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Gemifloxacin (GMF) is a fluoroquinolone antibiotic that inhibits bacterial DNA gyrase and topoisomerase IV. The aim of this study was to investigate the anti-metastatic activities of GMF and its possible mechanisms of action, with a special focus on the induction of mesenchymal–epithelial transition (MET). The human breast adenocarcinoma cell lines MDA-MB-231 and MDA-MB-453 were used to assess the anti-metastatic activity of GMF on cell migration and invasion and in scratch wound-healing assays. The effects of GMF on the MET and its regulatory nuclear factor κB (NF-κB)/Snail pathway were assessed. The in vivo anti-metastatic effect of GMF was also evaluated in an animal model. This study demonstrated that GMF inhibited the migration and invasion of MDA-MB-231 and MDA-MB-453 cells and induced the MET. GMF suppressed the activation of NF-κB, as well as the cell migration and invasion induced by tumor necrosis factor α (TNF-α). GMF was shown to inhibit the phosphorylation of the inhibitor of κB (IκB) and the translocation of NF-κB/Snail in both cancer cell lines. This study showed that the Raf kinase inhibitor protein (RKIP), an inhibitor of IκB kinase, is upregulated after GMF treatment. Inhibition of RKIP by small hairpin RNA transfection significantly decreased the inhibitory effect of GMF on the NF-κB/Snail pathway and also inhibited cell migration and invasion. Overexpression of Snail suppressed GMF-mediated metastasis inhibition and E-cadherin upregulation. An animal model revealed that GMF effectively inhibits lipopolysaccharide-mediated metastasis in mice. This study has demonstrated that GMF might be a novel anticancer agent for the prevention and treatment of metastasis in breast cancer.
GMF inhibits the migration and invasion of human breast adenocarcinoma cells.
GMF induces MET by reducing NF-κB and Snail activation and by increasing RKIP levels.
GMF has potential clinical implication as an anti-metastatic agent for breast cancer.
KeywordsGemifloxacin Breast cancer Metastasis NF-κB RKIP
Nuclear factor κB
Raf kinase inhibitor protein
Fetal bovine serum
Tumor necrosis factor α
Polymerase chain reaction
Small hairpin RNA
Hematoxylin and eosin
This study is supported by grants from the National Science Council of Taiwan (NSC 102-2628-B-037-002-MY3) and Excellence for Cancer Research Center Grant, the Department of Health, Executive Yuan, Taipei, Taiwan (DOH102-TD-C-111-002) and Kaohsiung Medical University Research Foundation (KMUER008 and KMU-Q102017) and Kaohsiung Municipal Ta-Tung Hospital (KMTTH-1-99-028). The authors thank the Center for Resources, Research, and Development of Kaohsiung Medical University for their support.
Conflict of interest
There are no potential conflicts of interest.
- 8.Yamaguchi N, Ito T, Azuma S, Ito E, Honma R, Yanagisawa Y, Nishikawa A, Kawamura M, Imai J, Watanabe S et al (2009) Constitutive activation of nuclear factor-kappaB is preferentially involved in the proliferation of basal-like subtype breast cancer cell lines. Cancer Sci 100:1668–1674PubMedCrossRefGoogle Scholar
- 22.Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR et al (2011) Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 52:427–431PubMedCrossRefGoogle Scholar
- 25.Paul S, DeCastro AJ, Lee HJ, Smolarek AK, So JY, Simi B, Wang CX, Zhou R, Rimando AM, Suh N (2010) Dietary intake of pterostilbene, a constituent of blueberries, inhibits the beta-catenin/p65 downstream signaling pathway and colon carcinogenesis in rats. Carcinogenesis 31:1272–1278PubMedCrossRefGoogle Scholar
- 35.Ren G, Baritaki S, Marathe H, Feng J, Park S, Beach S, Bazeley PS, Beshir AB, Fenteany G, Mehra R et al (2012) Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res 72:3091–3104PubMedCrossRefGoogle Scholar