title: Redox-modulating agents target NOX2-dependent IKKε oncogenic kinase expression and proliferation in human breast cancer cell lines.
abstract: Oxidative stress is considered a causative factor in carcinogenesis, but also in the development of resistance to current chemotherapies. The appropriate usage of redox-modulating compounds is limited by the lack of knowledge of their impact on specific molecular pathways. Increased levels of the IKKε kinase, as a result of gene amplification or aberrant expression, are observed in a substantial number of breast carcinomas. IKKε not only plays a key role in cell transformation and invasiveness, but also in the development of resistance to tamoxifen. Here, we studied the effect of in vitro treatment with the redox-modulating triphenylmethane dyes, Gentian Violet and Brilliant Green, and nitroxide Tempol on IKKε expression and cell proliferation in the human breast cancer epithelial cell lines exhibiting amplification of IKKε, MCF-7 and ZR75.1. We show that Gentian Violet, Brilliant Green and Tempol significantly decrease intracellular superoxide anion levels and inhibit IKKε expression and cell viability. Treatment with Gentian Violet and Brilliant Green was associated with a reduced cyclin D1 expression and activation of caspase 3 and/or 7. Tempol decreased cyclin D1 expression in both cell lines, while activation of caspase 7 was only observed in MCF-7 cells. Silencing of the superoxide-generating NOX2 NADPH oxidase expressed in breast cancer cells resulted in the significant reduction of IKKε expression. Taken together, our results suggest that redox-modulating compounds targeting NOX2 could present a particular therapeutic interest in combination therapy against breast carcinomas exhibiting IKKε amplification.
authors.affiliation: CRCHUM - Centre Hospitalier de l'Université de Montréal, 900 Rue Saint Denis, Montréal, QC, Canada H2X 0A9. Electronic address: esperance.mukawera.chum@ssss.gouv.qc.ca.
authors.forename: Espérance
authors.initials: E
authors.lastname: Mukawera
authors.affiliation: CRCHUM - Centre Hospitalier de l'Université de Montréal, 900 Rue Saint Denis, Montréal, QC, Canada H2X 0A9. Electronic address: chartiers@live.fr.
authors.forename: Stefany
authors.initials: S
authors.lastname: Chartier
authors.affiliation: CRCHUM - Centre Hospitalier de l'Université de Montréal, 900 Rue Saint Denis, Montréal, QC, Canada H2X 0A9; Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada H3C 3J7. Electronic address: virginie@gmail.com.
authors.forename: Virginie
authors.initials: V
authors.lastname: Williams
authors.affiliation: Department of Pharmacology and Chemical Biology, Vascular Medicine Institute, University of Pittsburgh, 200 Lothop Street, Pittsburgh, PA 15213, USA. Electronic address: pagano@pitt.edu.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pagano
authors.affiliation: CRCHUM - Centre Hospitalier de l'Université de Montréal, 900 Rue Saint Denis, Montréal, QC, Canada H2X 0A9; Institut Du Cancer, 900 Rue Saint Denis, Montréal, QC, Canada H2X 0A9. Electronic address: rejean.lapointe@umontreal.ca.
authors.forename: Réjean
authors.initials: R
authors.lastname: Lapointe
authors.affiliation: CRCHUM - Centre Hospitalier de l'Université de Montréal, 900 Rue Saint Denis, Montréal, QC, Canada H2X 0A9; Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada H3C 3J7. Electronic address: nathalie.grandvaux@umontreal.ca.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Grandvaux
mesh_terms: D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005840:Gentian Violet / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013113:Spin Labels; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; D003497:Cyclic N-Oxides; D008562:Membrane Glycoproteins; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; D013113:Spin Labels; D013481:Superoxides; D019938:Cyclin D1; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D051550:I-kappa B Kinase; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; C006798:brilliant green; D005840:Gentian Violet; C001803:tempol
keywords: Breast cancer; Cell growth; IKKε; NADPH oxidase; Tempol; Triphenylmethane dyes