title: Divergent targets of glycolysis and oxidative phosphorylation result in additive effects of metformin and starvation in colon and breast cancer.
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.
authors.affiliation: CNR Institute of Molecular Bioimaging and Physiology (IBFM), Milan, Section of Genoa, Genoa, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marini
authors.affiliation: Oncology lab, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bianchi
authors.affiliation: Nuclear Medicine, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Ambra
authors.initials: A
authors.lastname: Buschiazzo
authors.affiliation: Biochemistry Lab, Department of Pharmacy, University of Genoa, Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ravera
authors.affiliation: Oncology lab, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Martella
authors.affiliation: Nuclear Medicine, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bottoni
authors.affiliation: Core facility, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Petretto
authors.affiliation: Animal facility, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.affiliation: Nuclear Medicine, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Monteverde
authors.affiliation: Nuclear Medicine, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Selene
authors.initials: S
authors.lastname: Capitanio
authors.affiliation: Core facility, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: Inglese
authors.affiliation: Integrated oncological therapies, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.affiliation: Nuclear Medicine, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bongioanni
authors.affiliation: Nuclear Medicine, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Garaboldi
authors.affiliation: Statistics and Epidemiology Unit, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bruzzi
authors.affiliation: Nuclear Medicine, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Orengo
authors.affiliation: Oncology lab, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Lizzia
authors.initials: L
authors.lastname: Raffaghello
authors.affiliation: Nuclear Medicine, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Gianmario
authors.initials: G
authors.lastname: Sambuceti
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D008687:Metformin; D019311:Staurosporine; D005947:Glucose