Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2014) 35 S16.3 | DOI: 10.1530/endoabs.35.S16.3

ECE2014 Symposia Metformin: old dog, new tricks (3 abstracts)

Antitumoral effects of metformin on cancer stem cells: identification of novel molecular targets

Roberto Wurth 1 , Marta Gritti 2 , Marina Angelini 2 , Federica Barbieri 1 , Michele Mazzanti 2 & Tullio Florio 1

1Department of Internal Medicine, University of Genova, Genova, Italy; 2Department of Biosciences, University of Milano, Milano, Italy.

Epidemiological and preclinical studies propose that metformin, a first-line drug for type- 2 diabetes, exerts direct antitumoral activity. Although several clinical trials are currently ongoing, the molecular mechanisms of this effect are unknown. The AMP-activated kinase-dependent pathway, and the down-stream effectors (e.g. mTOR) are considered the main effectors. Several studies reported the involvement of, in metformin metabolic activity. Nevertheless, contrasting evidences were obtained on their role in metformin activity in tumor cells, and recently several reports showed AMPK-independent antiproliferative activity. Here we show that chloride intracellular channel 1 (CLIC1) is a direct target of metformin to block proliferation of human glioblastoma (GBM) cells, selectively interfering with cancer stem cell (CSC) subpopulation. These effects phenocopy metformin-mediated inhibition of CLIC1 chloride current, which is specifically dependent on membrane translocation and activation of this channel during the cell cycle. Metformin inhibition of CLIC1 activity, during its transient membrane insertion, arrests the transition from G1 to S phases. Furthermore, point mutation of the putative CLIC1 pore region impairs metformin interaction with CLIC1, highlighting an inhibitory activity from the extracellular side. This effect is rather specific for CSC, since no antiproliferative effects of metformin were observed on human normal stem cells. These findings highlight the role of CLIC1 as a principal target of metformin’s antiproliferative activity in human CSCs, paving the way for novel and needed pharmacological approach for cancer treatment treatment.

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