Resistance to glucose starvation as metabolic trait of platinum-resistant human epithelial ovarian cancer cells
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Anna Pastò1, Anna Pagotto1, Giorgia Pilotto1, Angela De Paoli2, Gian Luca De Salvo2, Alessandra Baldoni2, Maria Ornella Nicoletto2, Francesca Ricci3, Giovanna Damia3, Chiara Bellio1, Stefano Indraccolo2,*, Alberto Amadori1,2,*
1Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
2Istituto Oncologico Veneto IRCCS, Padova, Italy
3Laboratory of Molecular Pharmacology, Oncology Department, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
*These authors contributed equally to this work
Stefano Indraccolo, email: email@example.com
Anna Pastò, email: firstname.lastname@example.org
Keywords: glucose addiction, platinum resistance, ovarian cancer, metabolism, autophagy
Received: August 31, 2016 Accepted: December 15, 2016 Published: December 23, 2016
Deregulated glucose metabolism is observed in cancer but whether this metabolic trait influences response to or is modulated by cytotoxic drugs is unknown. We show here that tumor cells from epithelial ovarian cancer (EOC) patients can be categorized, according to their in vitro viability under glucose starvation, into glucose deprivation-sensitive (glucose-addicted, GA) and glucose deprivation-resistant (glucose non-addicted, GNA). When EOC cells were cultured in the absence of glucose, all samples from platinum (PLT)-sensitive patients felt into the GA group; they disclosed higher expression of glucose metabolism enzymes, higher proliferation rates and in vitro sensitivity to PLT. Moreover, GA patients showed reduced multi-drug resistance pump expression and autophagy, compared to GNA samples. The close association between PLT sensitivity and glucose metabolic profile was confirmed in a xenograft model, where a stringent parallelism between PLT sensitivity/resistance and glucose metabolism was identified. Finally, in a cohort of naïve EOC patients categorized as GA or GNA at diagnosis, Kaplan Meier curves showed that the GA phenotype was associated with significantly better progression-free survival, compared to GNA patients.
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