Marta Targosz-Korecka1, Katarzyna Ewa Malek-Zietek2, Damian Kloska3, Zenon Rajfur4, Ewa Łucja Stepien5, Anna Grochot-Przeczek6, Marek Szymonski2. 1. Department of Physics of Nanostructures and Nanotechnology, Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, Krakow, Poland. Electronic address: marta.targosz-korecka@uj.edu.pl. 2. Department of Physics of Nanostructures and Nanotechnology, Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, Krakow, Poland. 3. Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. 4. Department of Molecular and Interfacial Biophysics, Faculty of Physics, Astronomy and Applied Computer Science, Krakow, Poland. 5. Department of Medical Physics, Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, Krakow, Poland. 6. Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. Electronic address: anna.grochot-przeczek@uj.edu.pl.
Abstract
BACKGROUND: Epidemiologic studies suggest that diabetes is associated with an increased risk of cancer. Concurrently, clinical trials have shown that metformin, which is a first-line antidiabetic drug, displays anticancer activity. The underlying mechanisms for these effects are, however, still not well recognized. METHODS: Methods based on atomic force microscopy (AFM) were used to directly evaluate the influence of metformin on the nanomechanical and adhesive properties of endothelial and cancer cells in chronic hyperglycemia. AFM single-cell force spectroscopy (SCFS) was used to measure the total adhesion force and the work of detachment between EA.hy926 endothelial cells and A549 lung carcinoma cells. Nanoindentation with a spherical AFM probe provided information about the nanomechanical properties of cells, particularly the length and grafting density of the glycocalyx layer. Fluorescence imaging was used for glycocalyx visualization and monitoring of E-selectin and ICAM-1 expression. RESULTS: SCFS demonstrated that metformin attenuates adhesive interactions between EA.hy926 endothelial cells and A549 lung carcinoma cells in chronic hyperglycemia. Nanoindentation experiments, confirmed by confocal microscopy imaging, revealed metformin-induced recovery of endothelial glycocalyx length and density. The recovery of endothelial glycocalyx was correlated with a decrease in the surface expression of E-selectin and ICAM-1. CONCLUSION: Our results identify metformin-induced endothelial glycocalyx restoration as a key factor responsible for the attenuation of adhesion between EA.hy926 endothelial cells and A549 lung carcinoma cells. GENERAL SIGNIFICANCE: Metformin-induced glycocalyx restoration and the resulting attenuation of adhesive interactions between the endothelium and cancer cells may account for the antimetastatic properties of this drug.
BACKGROUND: Epidemiologic studies suggest that diabetes is associated with an increased risk of cancer. Concurrently, clinical trials have shown that metformin, which is a first-line antidiabetic drug, displays anticancer activity. The underlying mechanisms for these effects are, however, still not well recognized. METHODS: Methods based on atomic force microscopy (AFM) were used to directly evaluate the influence of metformin on the nanomechanical and adhesive properties of endothelial and cancer cells in chronic hyperglycemia. AFM single-cell force spectroscopy (SCFS) was used to measure the total adhesion force and the work of detachment between EA.hy926 endothelial cells and A549lung carcinoma cells. Nanoindentation with a spherical AFM probe provided information about the nanomechanical properties of cells, particularly the length and grafting density of the glycocalyx layer. Fluorescence imaging was used for glycocalyx visualization and monitoring of E-selectin and ICAM-1 expression. RESULTS: SCFS demonstrated that metformin attenuates adhesive interactions between EA.hy926 endothelial cells and A549lung carcinoma cells in chronic hyperglycemia. Nanoindentation experiments, confirmed by confocal microscopy imaging, revealed metformin-induced recovery of endothelial glycocalyx length and density. The recovery of endothelial glycocalyx was correlated with a decrease in the surface expression of E-selectin and ICAM-1. CONCLUSION: Our results identify metformin-induced endothelial glycocalyx restoration as a key factor responsible for the attenuation of adhesion between EA.hy926 endothelial cells and A549lung carcinoma cells. GENERAL SIGNIFICANCE: Metformin-induced glycocalyx restoration and the resulting attenuation of adhesive interactions between the endothelium and cancer cells may account for the antimetastatic properties of this drug.
Authors: Edmund Y M Chung; Katie Trinh; Jennifer Li; Sebastian Hayden Hahn; Zoltan H Endre; Natasha M Rogers; Stephen I Alexander Journal: Front Cardiovasc Med Date: 2022-05-20
Authors: Marina M Ziganshina; Ekaterina L Yarotskaya; Nicolai V Bovin; Stanislav V Pavlovich; Gennady T Sukhikh Journal: Int J Mol Sci Date: 2020-04-26 Impact factor: 5.923