Metformin impairs glucose consumption and survival in Calu-1 cells by Direct Inhibition of Hexokinase-II

Barbara Salani, Cecilia Marini, Alberto Del Rio, Silvia Ravera, Michela Massollo, Anna Maria Orengo, Adriana Amaro, Mario Passalacqua, Sara Maffioli, Ulrich Pfeffer, Renzo Cordera, Davide Maggi, Gianmario Sambuceti

Research output: Contribution to journalArticle

Abstract

The anti-hyperglycaemic drug metformin has important anticancer properties as shown by the direct inhibition of cancer cells proliferation. Tumor cells avidly use glucose as a source for energy production and cell building blocks. Critical to this phenotype is the production of glucose-6-phosphate (G6P), catalysed by hexokinases (HK) I and II, whose role in glucose retention and metabolism is highly advantageous for cell survival and proliferation. Here we show that metformin impairs the enzymatic function of HKI and II in Calu-1 cells. This inhibition virtually abolishes cell glucose uptake and phosphorylation as documented by the reduced entrapment of 18F-fluorodeoxyglucose. In-silicomodels indicate that this action is due to metformin capability to mimic G6P features by steadily binding its pocket in HKII. The impairment of this energy source results in mitochondrial depolarization and subsequent cell death. These results could represent a starting point to open effective strategies in cancer prevention and treatment.

Original languageEnglish
Article number2070
JournalScientific Reports
Volume3
DOIs
Publication statusPublished - Jun 25 2013

ASJC Scopus subject areas

  • General
  • Medicine(all)

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    Salani, B., Marini, C., Del Rio, A., Ravera, S., Massollo, M., Orengo, A. M., Amaro, A., Passalacqua, M., Maffioli, S., Pfeffer, U., Cordera, R., Maggi, D., & Sambuceti, G. (2013). Metformin impairs glucose consumption and survival in Calu-1 cells by Direct Inhibition of Hexokinase-II. Scientific Reports, 3, [2070]. https://doi.org/10.1038/srep02070