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.
Highlights
Autophagy is a multi-step recycling process that maintains cell and tissue homeostasis regulated by molecular components encoded by autophagy-related genes (ATGs) [1]
Starting from these considerations, we explored the effect of metformin on proliferation and autophagy in breast and cervical cancer cell lines where we observed a reduction of cellular replication rate correlated to an inhibition of glutamine metabolism, ammonia production and ammonia-induced autophagy
Observed that metformin reduces proliferation of Ca Ski and Me180 but not of HeLa cells. These results suggest that metformin can, directly or indirectly, alter ammonia production in breast and cervical cancer cells
Summary
Autophagy is a multi-step recycling process that maintains cell and tissue homeostasis regulated by molecular components encoded by autophagy-related genes (ATGs) [1]. Three principal forms of autophagy have been identified: microautophagy, macroautophagy and chaperone-mediated autophagy [2]. Are packed into cytosolic vesicles (autophagosomes), which are delivered to lysosomes in order to form double membrane vesicles (autolysosomes). In these structures, the autophagosomal content is digested by lysosomal hydrolases and the products are re-cycled back to cytosol in order to build up new molecules [3]. Autophagy promotes cancer resistance to radiation and chemotherapic treatments [5,6,7] and the abrogation of autophagic machinery renders cervical cancer cells more sensitive to cisplatin [8]
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