Divergent targets of glycolysis and oxidative phosphorylation result in additive effects of metformin and starvation in colon and breast cancer

Cecilia Marini, Giovanna Bianchi, Ambra Buschiazzo, Silvia Ravera, Roberto Martella, Gianluca Bottoni, Andrea Petretto, Laura Emionite, Elena Monteverde, Selene Capitanio, Elvira Inglese, Marina Fabbi, Francesca Bongioanni, Lucia Garaboldi, Paolo Bruzzi, Anna Maria Orengo, Lizzia Raffaghello, Gianmario Sambuceti

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Abstract

Emerging evidence demonstrates that targeting energy metabolism is a promising strategy to fight cancer. Here we show that combining metformin and short-term starvation markedly impairs metabolism and growth of colon and breast cancer. The impairment in glycolytic flux caused by starvation is enhanced by metformin through its interference with hexokinase II activity, as documented by measurement of 18F-fluorodeoxyglycose uptake. Oxidative phosphorylation is additively compromised by combined treatment: metformin virtually abolishes Complex I function; starvation determines an uncoupled status of OXPHOS and amplifies the activity of respiratory Complexes II and IV thus combining a massive ATP depletion with a significant increase in reactive oxygen species. More importantly, the combined treatment profoundly impairs cancer glucose metabolism and virtually abolishes lesion growth in experimental models of breast and colon carcinoma. Our results strongly suggest that energy metabolism is a promising target to reduce cancer progression.

Original languageEnglish
Article number19569
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Jan 22 2016

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Marini, C., Bianchi, G., Buschiazzo, A., Ravera, S., Martella, R., Bottoni, G., Petretto, A., Emionite, L., Monteverde, E., Capitanio, S., Inglese, E., Fabbi, M., Bongioanni, F., Garaboldi, L., Bruzzi, P., Orengo, A. M., Raffaghello, L., & Sambuceti, G. (2016). Divergent targets of glycolysis and oxidative phosphorylation result in additive effects of metformin and starvation in colon and breast cancer. Scientific Reports, 6, [19569]. https://doi.org/10.1038/srep19569