Antitumoral effects of metformin on cancer stem cells
ANNALES D’ENDOCRINOLOGIE Vol 76 - N° 4 P. 296 - septembre 2015 T. Florio, Pr
Epidemiological and preclinical studies suggested that metformin, the first-line drug for type-2 diabetes, exerts direct antitumoral activity. Clinical trials are currently ongoing for several human tumors, although the molecular mechanisms of metformin antiproliferative activity are still not completely identified. Several studies reported the involvement of AMP-activated kinase-dependent pathway, and the downstream effectors (e.g., mTOR) in metformin metabolic activity. Nevertheless, contrasting evidence was obtained on the involvement of this pathway in metformin antitumor effect, and several reports showed AMPK-independent antiproliferative activity. According to the hierarchical theory of tumorigenesis, cancer stem cells (CSC) are considered the real pharmacological target to obtain cancer remission. Here, we show that metformin inhibits proliferation of human glioblastoma cells, selectively acting on CSC viability, through the direct inhibition of chloride intracellular channel-1 (CLIC1). CLIC1 chloride current is specifically induced upon translocation and transient membrane insertion of this channel during cell cycle progression. By means of patch clamp experiments, we show that the antiproliferative effect of metformin correlates with the inhibition of CLIC1 current, causing the arrest of the G1-S transition. Furthermore, point mutation of the putative CLIC1 pore region impairs metformin interaction with the channel, highlighting an inhibitory activity from the extracellular side. This effect is rather specific for CSC, since no cytotoxic effects, using metformin at the same concentration, were observed in 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.
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