Abstract
Metformin is the most widely used antidiabetic drug because of its proven efficacy and limited secondary effects. Interestingly, recent studies have reported that metformin can block the growth of different tumor types. Here, we show that metformin exerts antiproliferative effects on melanoma cells, whereas normal human melanocytes are resistant to these metformin-induced effects. To better understand the basis of this antiproliferative effect of metformin in melanoma, we characterized the sequence of events underlying metformin action. We showed that 24 h metformin treatment induced a cell cycle arrest in G0/G1 phases, while after 72 h, melanoma cells underwent autophagy as demonstrated by electron microscopy, immunochemistry, and by quantification of the autolysosome-associated LC3 and Beclin1 proteins. In addition, 96 h post metformin treatment we observed robust apoptosis of melanoma cells. Interestingly, inhibition of autophagy by knocking down LC3 or ATG5 decreased the extent of apoptosis, and suppressed the antiproliferative effect of metformin on melanoma cells, suggesting that apoptosis is a consequence of autophagy. The relevance of these observations were confirmed in vivo, as we showed that metformin treatment impaired the melanoma tumor growth in mice, and induced autophagy and apoptosis markers. Taken together, our data suggest that metformin has an important impact on melanoma growth, and may therefore be beneficial in patients with melanoma.
Highlights
To this purpose, we have been interested in studying the effect of the oral antidiabetic drug, metformin, on melanoma
The apoptosis inductor staurosporine was found to induce apoptosis but not autophagy. These results were confirmed by quantification of western blots using a Fuji Film, Multi Gauge Ver 3.0 software (Fuji Film, Tokyo, Japan) (Figure 3b, lower part). These results indicate that metformin induces a concomitant induction of autophagy and apoptosis processes in melanoma cells, both of which are involved in cell death
Contrary to normal human melanocytes, drastic inhibition of cell viability mediated by metformin is observed in four different melanoma cell lines independent of the mutational status or melanoma development stage, and in two primary melanoma cell cultures freshly isolated from patients
Summary
We have been interested in studying the effect of the oral antidiabetic drug, metformin, on melanoma. Metformin belongs to the family of biguanide and is the most widely used antidiabetic drug in the world.[2] The effect of metformin on glucose homeostasis has been explained through reduced hepatic gluconeogenesis and increased glucose uptake in skeletal muscles.[3,4] This drug has the major clinical advantage of not inducing hypoglycemia and being tolerated very well It is associated with only very low incidence of lactic acidosis (1/30 000) predominantly in patients with altered kidney or liver functions.[5] The mechanism through which metformin reduces hepatic glucose production requires LKB1, which controls the AMPK (AMP-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway and neoglucogenic genes.[6]. We wished to study the effect of metformin on melanoma cell viability, and to further investigate the molecular mechanisms by which metformin exerts its action on melanoma cells
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