title: Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment.
abstract: In order to improve our understanding of the potential preventive and therapeutic role of metformin, the present study aimed to investigate the capability of low-dose metformin in the efficient inhibition of cancer development and the reduction of the metastasis of endometrial adenocarcinoma type I and primary endometrial epithelial cells (eEPs), with the drug acting as a treatment in a hyperinsulinemic environment exposed to high and normal glucose conditions. The Ishikawa endometrial adenocarcinoma cell line and primary eEPs were exposed to an environment with high (17 mM) or normal glucose (5 mM) and treated with insulin, low-dose metformin (0.1 mM) or a combined treatment. Metastatic potential was assessed by migration and invasion assays, and relative cell proliferation was determined. Metformin at a low dose potently inhibited the insulin action, decreasing the ability of the endometrial cancer (EC) cell line to migrate and invade in a high and normal glucose environment, and decreasing the migration ability of the primary eEPs. In the EC cell line, the insulin treatment increased the proliferation, without any subsequent reduction of proliferation by the addition of 0.1 mM metformin; however, relative cell proliferation sensitivity to metformin was observed in the range between 1 and 5 mM regardless of the glucose concentration present. Overall, metformin at 0.1 mM is not efficient enough to decrease the proliferation in an EC cell line. However, at this concentration, metformin can inhibit the insulin action in endometrial epithelial cancer cells, demonstrating an anti-metastatic effect in high and normal glucose environments.
authors.affiliation: Laboratory of Molecular Endocrine Biology and Tumor Biology, Department of Physiology, Institute of Basic Sciences of Health, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil; Laboratory of Molecular Obstetrics and Gynecology, Experimental Research Center, Department of Obstetrics and Gynecology, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil; Department of Gynecological Endocrinology and Reproductive Medicine, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Amanda
authors.initials: A
authors.lastname: de Barros Machado
authors.affiliation: Laboratory of Molecular Endocrine Biology and Tumor Biology, Department of Physiology, Institute of Basic Sciences of Health, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil; Laboratory of Molecular Obstetrics and Gynecology, Experimental Research Center, Department of Obstetrics and Gynecology, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil.
authors.forename: Vania
authors.initials: V
authors.lastname: Dos Reis
authors.affiliation: Department of Gynecological Endocrinology and Reproductive Medicine, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Weber
authors.affiliation: Department of Gynecological Endocrinology and Reproductive Medicine, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Jauckus
authors.affiliation: Laboratory of Molecular Endocrine Biology and Tumor Biology, Department of Physiology, Institute of Basic Sciences of Health, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil; Laboratory of Molecular Obstetrics and Gynecology, Experimental Research Center, Department of Obstetrics and Gynecology, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil.
authors.forename: Ilma Simoni
authors.initials: IS
authors.lastname: Brum
authors.affiliation: Laboratory of Molecular Endocrine Biology and Tumor Biology, Department of Physiology, Institute of Basic Sciences of Health, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil; Laboratory of Molecular Obstetrics and Gynecology, Experimental Research Center, Department of Obstetrics and Gynecology, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil.
authors.forename: Helena
authors.initials: H
authors.lastname: von Eye Corleta
authors.affiliation: Department of Gynecological Endocrinology and Reproductive Medicine, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Strowitzki
authors.affiliation: Laboratory of Molecular Endocrine Biology and Tumor Biology, Department of Physiology, Institute of Basic Sciences of Health, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil; Laboratory of Molecular Obstetrics and Gynecology, Experimental Research Center, Department of Obstetrics and Gynecology, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90050-170, Brazil; Department of Gynecological Endocrinology and Reproductive Medicine, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Edison
authors.initials: E
authors.lastname: Capp
authors.affiliation: Department of Gynecological Endocrinology and Reproductive Medicine, University Hospital Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Ariane
authors.initials: A
authors.lastname: Germeyer
keywords: cancer development; endometrial cancer; glucose; hyperinsulinemia; metastasis; metformin