Functional characterization of the glucose transporter GLUT12 and study of its expression in cancer and alzheimer disease

Résumé

Title: Functional characterization of the facilitative glucose transporter GLUT12 and study of its expression in Cancer and Alzheimer disease Author: Jonai Pujol Gimenez Year: 2014 Faculty of Pharmacy, Department of Nutrition, Food Science and Physiology, University of Navarra GLUT12 belongs to the facilitative glucose transporter family GLUT/SLC2A. It was cloned from a breast cancer adenocarcinoma cell line (MCF-7). Functional studies through inhibition experiments showed that GLUT12 transports 2-DOG, glucose, galactose and fructose, and that GLUT12 can also transport glucose against its diffusion gradient, coupling the transport to H+. GLUT12 has been described as a secondary insulin-sensitive transporter and thus, its involvement in impaired insulin response associated pathologies have been studied. In addition, GLUT12 expression has been described in human breast tumours and prostate adenocarcinomas, and it has been proposed that GLUT12 could be one of the main glucose transporters involved in the glycolytic metabolism characteristic of cancer cells. Based on those data, the objectives for the present work were: 1) to study the functional properties of GLUT12 and 2) to analyse GLUT12 expression in pathologies in which normal glucose metabolism is compromised, such as cancer and Alzheimer. Our functional studies showed that GLUT12 is a low selectivity transporter, transporting glucose=α-MG (a specific substrate of the Na+/glucose cotransporter)>2-DOG >galactose =fructose. GLUT12 is electrogenic and glucose-induced current are driven by a Cl- conductance, which is uncoupled to the substrate transport. Inmunohistochemical determinations revealed that GLUT12 is expressed in a series of cancer cell lines, supporting its role in the glycolytic metabolism characteristic of these cells. Western-blot experiments showed that GLUT12 is expressed in brain of normal aged people, but not in young brains, and over-expressed in Alzheimer¿s patients brain, indicating that GLUT12 expression in brain would be related to aging, which is the main risk factor for neurodegenerative diseases. Overall, our results demonstrate that GLUT12 has unique functional features, never described before for other glucose transporters, and that its expression seems to be related to the development of diseases in which the normal glucose metabolism is impaired, suggesting that GLUT12 expression could be part of the cellular response to a compromised glucose metabolism.