title: Plumbagin Suppresses the Invasion of HER2-Overexpressing Breast Cancer Cells through Inhibition of IKKα-Mediated NF-κB Activation.
abstract: HER2-overexpressing breast cancers account for about 30% of breast cancer occurrences and have been correlated with increased tumor aggressiveness and invasiveness. The nuclear factor-κB (NF-κB) is overexpressed in a subset of HER2-positive breast cancers and its upregulation has been associated with the metastatic potential of HER2-overexpressing tumors. The present study aimed at determining the potential of plumbagin, a naturally occurring naphthoquinone, to inhibit the invasion of HER2-overexpressing breast cancer cells and determine the involvement of NF-κB inhibition in plumbagin-mediated cell invasion suppression. In the present research we showed that plumbagin inhibited the transcriptional activity of NF-κB in HER2-positive breast cancer cells. The suppression of NF-κB activation corresponded with the inhibition of NF-κB p65 phosphorylation and downregulation of NF-κB-regulated matrix metalloproteinase 9 (MMP-9) expression. Plumbagin suppressed the invasion of HER2-overexpressing breast cancer cells and the inhibition of cell invasion was associated with the ability of plumbagin to inhibit NF-κB transcriptional activity. The silencing of NF-κB p65 increased the sensitivity of HER2-overexpressing breast cancer cells to plumbagin-induced cell invasion inhibition. NF-κB inhibition was associated with IκB kinase α (IKKα) activity suppression and inhibition of IκBα phosphorylation and degradation. The knockdown of IKKα resulted in increased sensitivity of HER2-positive cells to plumbagin-induced suppression of NF-κB transcriptional activity and expression of MMP-9. In conclusion, plumbagin inhibits the invasion of HER2-overexpressing breast cancer cells through the inhibition of IKKα-mediated NF-κB activation and downregulation of NF-κB-regulated MMP-9 expression.
authors.affiliation: Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk & Medical University of Gdansk, Gdansk, Poland.|Laboratory of Human Physiology, Faculty of Health Sciences with Subfaculty of Nursing, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kawiak
authors.affiliation: Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk & Medical University of Gdansk, Gdansk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Domachowska
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009285:Naphthoquinones / Q000633:toxicity*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D051550:I-kappa B Kinase; D020780:Matrix Metalloproteinase 9; D009285:Naphthoquinones; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D051996:Transcription Factor RelA; D000097782:NF-kappaB-Inducing Kinase; C508053:ERBB2 protein, human; C014758:plumbagin