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

Scientific Reports
Cecilia MariniGianmario Sambuceti

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.

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Citations

Feb 18, 2017·Nutrients·Fedra Luciano-MateoJorge Joven
Aug 8, 2018·International Journal of Obesity : Journal of the International Association for the Study of Obesity·Elisa PrincipiSara Tavella
Sep 15, 2017·International Journal of Radiation Biology·Rainer J Klement
Aug 12, 2016·Clinical and Translational Medicine·Christoph HerbelVassiliki A Boussiotis
Apr 5, 2019·Oncology Letters·Lin Jin, Yanhong Zhou
Aug 21, 2018·Frontiers in Oncology·Thibault Le BourgeoisVassiliki A Boussiotis
Feb 17, 2019·Breast Cancer Research and Treatment·Hua ZhaoWong-Ho Chow
Nov 14, 2017·Complementary Medicine Research·Rainer Johannes Klement
Aug 4, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Andrea AloiaWerner J Kovacs
Dec 31, 2018·Redox Biology·Matilda LeeAndrea L Wong
Jan 11, 2020·Molecular Metabolism·Matteo BaucknehtCecilia Marini

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