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Cells 2019, 8(1), 49; https://doi.org/10.3390/cells8010049

Metformin Impairs Glutamine Metabolism and Autophagy in Tumour Cells

1
Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
2
Department of Cellular and Molecular Pathology, IRCCS San Raffaele, 00166 Rome, Italy
3
MEBIC Consortium, San Raffaele Rome Open University, 00166 Rome, Italy
*
Author to whom correspondence should be addressed.
Received: 21 December 2018 / Revised: 7 January 2019 / Accepted: 9 January 2019 / Published: 14 January 2019
(This article belongs to the Special Issue Autophagy in Tissue Injury and Homeostasis)
PDF [835 KB, uploaded 14 January 2019]   |   Review Reports

Abstract

Metformin 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.
Keywords: autophagy; cell death; glutaminase; metabolism; molecular rehabilitation. autophagy; cell death; glutaminase; metabolism; molecular rehabilitation.
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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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.

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