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Diabetic concentrations of metformin inhibit platelet-mediated ovarian cancer cell progression

2017; Impact Journals LLC; Volume: 8; Issue: 13 Linguagem: Inglês

10.18632/oncotarget.15348

1949-2553

Rafaela Erices, Sofía Cubillos, Raúl Aravena, Felice Santoro, Mónica Marquez, Renán Orellana, Carolina Ramírez, Pamela González, Patricia Fuenzalida, María Loreto Bravo, Bárbara Oliva, Sumie Kato, Carolina Ibáñez, Jorge Brañes, Erasmo Bravo, Catalina Alonso, Karen García, Clemente Arab, Vicente A. Torres, Alejandro Godoy, Jaime Pereira, Galdo Bustos, César Cárdenas, Mauricio Cuello, Gareth I. Owen,

FOXO transcription factor regulation

// Rafaela Erices 1, 2 , Sofía Cubillos 2 , Raúl Aravena 2, 3 , Felice Santoro 2 , Monica Marquez 2 , Renan Orellana 1, 15 , Carolina Ramírez 2 , Pamela González 2, 4 , Patricia Fuenzalida 2 , María Loreto Bravo 2, 4, 5 , Bárbara Oliva 2, 4 , Sumie Kato 1 , Carolina Ibañez 5, 6, 7 , Jorge Brañes 1 , Erasmo Bravo 8 , Catalina Alonso 8 , Karen García 7, 9 , Clemente Arab 10 , Vicente A. Torres 11, 16 , Alejandro S. Godoy 2, 12 , Jaime Pereira 6 , Galdo Bustos 13 , Julio Cesar Cardenas 13, 14 , Mauricio A. Cuello 1 , Gareth I. Owen 2, 4, 5, 7, 16 1 Division of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile 2 Department of Physiological Sciences, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile 3 Universidad Santo Tomás, Santiago, Chile 4 Biomedical Research Consortium of Chile, Santiago, Chile 5 Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile 6 Hematology and Oncology Department, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile 7 Center UC Investigation in Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile 8 Hospital Gustavo Fricke, Viña de Mar, Santiago, Chile 9 Hospital Sotero del Rio, Santiago, Chile 10 Hospital Luis Tisne, Santiago, Chile 11 Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile 12 Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA 13 Anatomy and Developmental Biology, Institute of Biomedical Science, Geroscience Center for Brain Health and Metabolism, University of Chile, Santiago, Chile 14 Buck Institute for Research on Aging, Novato, CA, USA 15 Universidad Bernardo OHiggins, Facultad de Salud, Departamento de Ciencias Químicas y Biológicas, General Gana, Santiago, Chile 16 Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile Correspondence to: Gareth I. Owen, email: gowen@bio.puc.cl Keywords: thrombocytosis, hemostasis, EA.hy926, SKOV3, UCI101 Received: July 27, 2016 Accepted: January 27, 2017 Published: February 15, 2017 ABSTRACT Clinical studies have suggested a survival benefit in ovarian cancer patients with type 2 diabetes mellitus taking metformin, however the mechanism by which diabetic concentrations of metformin could deliver this effect is still poorly understood. Platelets not only represent an important reservoir of growth factors and angiogenic regulators, they are also known to participate in the tumor microenvironment implicated in tumor growth and dissemination. Herein, we investigated if diabetic concentrations of metformin could impinge upon the previously reported observation that platelet induces an increase in the tube forming capacity of endothelial cells (angiogenesis) and upon ovarian cancer cell aggressiveness. We demonstrate that metformin inhibits the increase in angiogenesis brought about by platelets in a mechanism that did not alter endothelial cell migration. In ovarian cancer cell lines and primary cultured cancer cells isolated from the ascitic fluid of ovarian cancer patients, we assessed the effect of combinations of platelets and metformin upon angiogenesis, migration, invasion and cancer sphere formation. The enhancement of each of these parameters by platelets was abrogated by the present of metformin in the vast majority of cancer cell cultures tested. Neither metformin nor platelets altered proliferation; however, metformin inhibited the increase in phosphorylation of focal adhesion kinase induced by platelets. We present the first evidence suggesting that concentrations of metformin present in diabetic patients may reduce the actions of platelets upon both endothelial cells and cancer cell survival and dissemination.