Metformin Impairs Glutamine Metabolism and Autophagy in Tumour Cells

Serena Saladini, Michele Aventaggiato, Federica Barreca, Emanuela Morgante, Luigi Sansone, Matteo A Russo, Marco Tafani

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalCells
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 14 2019

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Keywords

  • Adaptor Proteins, Signal Transducing/metabolism
  • Ammonia/metabolism
  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Autophagy/drug effects
  • Cisplatin/pharmacology
  • Glutaminase/antagonists & inhibitors
  • Glutamine/metabolism
  • HeLa Cells
  • Humans
  • MCF-7 Cells
  • Metformin/pharmacology
  • Microtubule-Associated Proteins/metabolism
  • Neoadjuvant Therapy

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