Metformin Impairs Glutamine Metabolism and Autophagy in Tumour Cells
AbstractMetformin has been shown to inhibit glutaminase (GLS) activity and ammonia accumulation thereby reducing the risk of hepatic encephalopathy in type 2 diabetic patients. Since tumour cells are addicted to glutamine and often show an overexpression of glutaminase, we hypothesize that the antitumoral mechanism of metformin could be ascribed to inhibition of GLS and reduction of ammonia and ammonia-induced autophagy. Our results show that, in different tumour cell lines, micromolar doses of metformin prevent cell growth by reducing glutamate, ammonia accumulation, autophagy markers such as MAP1LC3B-II and GABARAP as well as degradation of long-lived proteins. Reduced autophagy is then accompanied by increased BECN1/BCL2 binding and apoptotic cell death. Interestingly, GLS-silenced cells reproduce the effect of metformin treatment showing reduced MAP1LC3B-II and GABARAP as well as ammonia accumulation. Since metformin is used as adjuvant drug to increase the efficacy of Cisplatin-based neoadjuvant chemotherapy, we co-treated tumour cells with micromolar doses of metformin in the presence of cisplatin observing a marked reduction of MAP1LC3B-II and an increase of caspase 3 cleavage. In conclusion, our work demonstrates that the anti-tumoral action of metformin is due to the inhibition of glutaminase and autophagy and could be used to improve the efficacy of chemotherapy.
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Saladini, S.; Aventaggiato, M.; Barreca, F.; Morgante, E.; Sansone, L.; Russo, M.A.; Tafani, M. Metformin Impairs Glutamine Metabolism and Autophagy in Tumour Cells. Cells 2019, 8, 49.
Saladini S, Aventaggiato M, Barreca F, Morgante E, Sansone L, Russo MA, Tafani M. Metformin Impairs Glutamine Metabolism and Autophagy in Tumour Cells. Cells. 2019; 8(1):49.Chicago/Turabian Style
Saladini, Serena; Aventaggiato, Michele; Barreca, Federica; Morgante, Emanuela; Sansone, Luigi; Russo, Matteo A.; Tafani, Marco. 2019. "Metformin Impairs Glutamine Metabolism and Autophagy in Tumour Cells." Cells 8, no. 1: 49.
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