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Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells

Background: Several mechanisms of action have been proposed to explain the apparent antineoplastic functions of metformin, many of which are observed at high concentrations that may not be reflective of achievable tissue concentrations. We propose that metformin at low concentrations functions to in...

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Autores principales: Schexnayder, Chandler, Broussard, Kiera, Onuaguluchi, Demitrius, Poché, Anthony, Ismail, Moamen, McAtee, LeFontae, Llopis, Shawn, Keizerweerd, Amber, McFerrin, Harris, Williams, Christopher
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274682/
https://www.ncbi.nlm.nih.gov/pubmed/30469399
http://dx.doi.org/10.3390/ijms19113692
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author Schexnayder, Chandler
Broussard, Kiera
Onuaguluchi, Demitrius
Poché, Anthony
Ismail, Moamen
McAtee, LeFontae
Llopis, Shawn
Keizerweerd, Amber
McFerrin, Harris
Williams, Christopher
author_facet Schexnayder, Chandler
Broussard, Kiera
Onuaguluchi, Demitrius
Poché, Anthony
Ismail, Moamen
McAtee, LeFontae
Llopis, Shawn
Keizerweerd, Amber
McFerrin, Harris
Williams, Christopher
author_sort Schexnayder, Chandler
collection PubMed
description Background: Several mechanisms of action have been proposed to explain the apparent antineoplastic functions of metformin, many of which are observed at high concentrations that may not be reflective of achievable tissue concentrations. We propose that metformin at low concentrations functions to inhibit ROS production and inflammatory signaling in breast cancer, thereby reducing metastasis. Methods: Using the highly invasive MDA-MB-231 breast carcinoma model, we ascertained the impact of metformin on cell viability by DNA content analysis and fluorescent dye exclusion. Migration and invasion assays were performed using a modified Boyden chamber assay and metastasis was ascertained using the chorioallantoic membrane (CAM) assay. PGE2 production was measured by Enzyme-Linked Immunosorbent Assay (ELISA). COX2 and ICAM1 levels were determined by flow cytometry immunoassay. Results: Metformin acutely decreased cell viability and caused G2 cell cycle arrest only at high concentrations (10 mM). At 100 µM, however, metformin reduced ICAM1 and COX2 expression, as well as reduced PGE2 production and endogenous mitochondrial ROS production while failing to significantly impact cell viability. Consequently, metformin inhibited migration, invasion in vitro and PGE2-dependent metastasis in CAM assays. Conclusion: At pharmacologically achievable concentrations, metformin does not drastically impact cell viability, but inhibits inflammatory signaling and metastatic progression in breast cancer cells.
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spelling pubmed-62746822018-12-15 Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells Schexnayder, Chandler Broussard, Kiera Onuaguluchi, Demitrius Poché, Anthony Ismail, Moamen McAtee, LeFontae Llopis, Shawn Keizerweerd, Amber McFerrin, Harris Williams, Christopher Int J Mol Sci Article Background: Several mechanisms of action have been proposed to explain the apparent antineoplastic functions of metformin, many of which are observed at high concentrations that may not be reflective of achievable tissue concentrations. We propose that metformin at low concentrations functions to inhibit ROS production and inflammatory signaling in breast cancer, thereby reducing metastasis. Methods: Using the highly invasive MDA-MB-231 breast carcinoma model, we ascertained the impact of metformin on cell viability by DNA content analysis and fluorescent dye exclusion. Migration and invasion assays were performed using a modified Boyden chamber assay and metastasis was ascertained using the chorioallantoic membrane (CAM) assay. PGE2 production was measured by Enzyme-Linked Immunosorbent Assay (ELISA). COX2 and ICAM1 levels were determined by flow cytometry immunoassay. Results: Metformin acutely decreased cell viability and caused G2 cell cycle arrest only at high concentrations (10 mM). At 100 µM, however, metformin reduced ICAM1 and COX2 expression, as well as reduced PGE2 production and endogenous mitochondrial ROS production while failing to significantly impact cell viability. Consequently, metformin inhibited migration, invasion in vitro and PGE2-dependent metastasis in CAM assays. Conclusion: At pharmacologically achievable concentrations, metformin does not drastically impact cell viability, but inhibits inflammatory signaling and metastatic progression in breast cancer cells. MDPI 2018-11-21 /pmc/articles/PMC6274682/ /pubmed/30469399 http://dx.doi.org/10.3390/ijms19113692 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Schexnayder, Chandler
Broussard, Kiera
Onuaguluchi, Demitrius
Poché, Anthony
Ismail, Moamen
McAtee, LeFontae
Llopis, Shawn
Keizerweerd, Amber
McFerrin, Harris
Williams, Christopher
Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells
title Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells
title_full Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells
title_fullStr Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells
title_full_unstemmed Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells
title_short Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells
title_sort metformin inhibits migration and invasion by suppressing ros production and cox2 expression in mda-mb-231 breast cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274682/
https://www.ncbi.nlm.nih.gov/pubmed/30469399
http://dx.doi.org/10.3390/ijms19113692
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