title: Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment.
abstract: A number of studies suggest that cancer stem cells are essential for tumour growth, and failure to target these cells can result in tumour relapse. As this population of cells has been shown to be resistant to radiation and chemotherapy, it is essential to understand their biology and identify new therapeutic approaches. Targeting cancer metabolism is a potential alternative strategy to counteract tumour growth and recurrence. Here we applied a proteomic and targeted metabolomic analysis in order to point out the main metabolic differences between breast cancer cells grown as spheres and thus enriched in cancer stem cells were compared with the same cells grown in adherent differentiating conditions. This integrated approach allowed us to identify a metabolic phenotype associated with the stem-like condition and shows that breast cancer stem cells (BCSCs) shift from mitochondrial oxidative phosphorylation towards fermentative glycolysis. Functional validation of proteomic and metabolic data provide evidences for increased activities of key enzymes of anaerobic glucose fate such as pyruvate kinase M2 isoform, lactate dehydrogenase and glucose 6-phopshate dehydrogenase in cancer stem cells as well as different redox status. Moreover, we show that treatment with 2-deoxyglucose, a well known inhibitor of glycolysis, inhibits BCSC proliferation when used alone and shows a synergic effect when used in combination with doxorubicin. In conclusion, we suggest that inhibition of glycolysis may be a potentially effective strategy to target BCSCs.
authors.affiliation: 1] School of Human and Social Science, 'Kore' University of Enna, Enna, Italy [2] Center of Excellence on Aging (Ce.S.I.), 'G. d'Annunzio' Foundation, Chieti, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Ciavardelli
authors.affiliation: 1] Center of Excellence on Aging (Ce.S.I.), 'G. d'Annunzio' Foundation, Chieti, Italy [2] Department of Experimental and Clinical Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Rossi
authors.affiliation: 1] Center of Excellence on Aging (Ce.S.I.), 'G. d'Annunzio' Foundation, Chieti, Italy [2] Department of Experimental and Clinical Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Barcaroli
authors.affiliation: Department of Surgical and Oncological Sciences, Laboratory of Cellular and Molecular Pathophysiology, University of Palermo, Palermo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Volpe
authors.affiliation: 1] Center of Excellence on Aging (Ce.S.I.), 'G. d'Annunzio' Foundation, Chieti, Italy [2] Department of Experimental and Clinical Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Consalvo
authors.affiliation: 1] Center of Excellence on Aging (Ce.S.I.), 'G. d'Annunzio' Foundation, Chieti, Italy [2] Department of Experimental and Clinical Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Zucchelli
authors.affiliation: 1] Center of Excellence on Aging (Ce.S.I.), 'G. d'Annunzio' Foundation, Chieti, Italy [2] Department of Experimental and Clinical Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.
authors.forename: A
authors.initials: A
authors.lastname: De Cola
authors.affiliation: Department of Surgical and Oncological Sciences, Laboratory of Cellular and Molecular Pathophysiology, University of Palermo, Palermo, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Scavo
authors.affiliation: Department of Surgical and Oncological Sciences, Laboratory of Cellular and Molecular Pathophysiology, University of Palermo, Palermo, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Carollo
authors.affiliation: 1] Center of Excellence on Aging (Ce.S.I.), 'G. d'Annunzio' Foundation, Chieti, Italy [2] Department of Experimental and Clinical Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.
authors.forename: D
authors.initials: D
authors.lastname: D'Agostino
authors.affiliation: 1] Center of Excellence on Aging (Ce.S.I.), 'G. d'Annunzio' Foundation, Chieti, Italy [2] Department of Experimental and Clinical Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Forlì
authors.affiliation: IRCCS S. Lucia, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: D'Aguanno
authors.affiliation: Department of Surgical and Oncological Sciences, Laboratory of Cellular and Molecular Pathophysiology, University of Palermo, Palermo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Todaro
authors.affiliation: Department of Surgical and Oncological Sciences, Laboratory of Cellular and Molecular Pathophysiology, University of Palermo, Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Stassi
authors.affiliation: Department of Experimental and Clinical Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Di Ilio
authors.affiliation: 1] Center of Excellence on Aging (Ce.S.I.), 'G. d'Annunzio' Foundation, Chieti, Italy [2] Department of Experimental and Clinical Sciences, 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy.
authors.forename: V
authors.initials: V
authors.lastname: De Laurenzi
authors.affiliation: 1] IRCCS S. Lucia, Rome, Italy [2] Department of Internal Medicine, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Urbani
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000378:metabolism*; D005260:Female; D006019:Glycolysis; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D011770:Pyruvate Kinase / Q000378:metabolism
chemical_list: D003847:Deoxyglucose; D007770:L-Lactate Dehydrogenase; D011770:Pyruvate Kinase