Differential effects of metformin on reductive activity and energy production in pituitary tumor cells compared to myoge
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ORIGINAL ARTICLE
Differential effects of metformin on reductive activity and energy production in pituitary tumor cells compared to myogenic precursors Giovanni Tulipano1 Simone Paghera1 Cristina Missale1 Andrea Giustina2 ●
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Received: 21 February 2020 / Accepted: 28 May 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose Given the multiple targets of metformin within cells, the mechanism by which it may exert a growth-inhibitory action on pituitary tumor cells in vitro remains to be explored. Previous research stressed metformin-induced changes in the activity of signaling pathways regulating cell growth and cell death. In this work, we investigated the effects of metformin on cell viability markers related to cell metabolic activity in rat pituitary tumor cells versus rat myogenic precursors as a model of normal proliferating somatic cells. Methods We designed our experiments in order to use the MTT reduction as a marker of cellular reductive activity and the total cellular ATP levels as a marker of energy supply during short incubations with different metabolic substrates (sodium pyruvate, D-glucose, L-glutamine, sodium citrate). Then, we extended the analysis to extracellular glucose consumption, extracellular medium acidification and pyruvate dehydrogenase (PDH) complex activity. Results Metformin was found to be effective in both cell types at the same concentrations, although the outcome of the treatment was quite the opposite. Unexpectedly, metformin increased the viability of subconfluent rat myoblasts. Rat pituitary tumor cells and myoblasts differed in the utilization of distinct metabolic substrates and the PDH complex activity. Metformin actions on reductive activity and ATP production were substrate-dependent. Conclusions Overall, this work points out that metformin actions at the cellular level depend on metabolic features and metabolic requirements of cells. The pyruvate metabolic branch point is most likely to play a main role in the variability of cell response to metformin. Keywords Metformin Cell metabolism Pituitary tumors Muscle Pyruvate Glutamine ●
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Introduction Pharmaco-epidemiologic studies and preclinical investigations have suggested that the biguanide metformin has antineoplastic activity and its potential as an adjuvant agent
Supplementary information The online version of this article (https:// doi.org/10.1007/s12020-020-02373-7) contains supplementary material, which is available to authorized users. * Giovanni Tulipano [email protected] 1
Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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San Raffaele Vita- Salute University – Head, Division of Endocrinology, IRCCS San Raffaele Hospital, Segrate, Italy
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in the treatment of endocrine tumors has been recently reviewed [1]. In vitro studies evidenced that metformin can inhibit the growth of rat pituitary tumor cells [2–4]. However, there are limited studies investigating th
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