Resistance to glucose starvation as metabolic trait of platinum-resistant human epithelial ovarian cancer cells

// Anna Pasto 1 , Anna Pagotto 1 , Giorgia Pilotto 1 , Angela De Paoli 2 , Gian Luca De Salvo 2 , Alessandra Baldoni 2 , Maria Ornella Nicoletto 2 , Francesca Ricci 3 , Giovanna Damia 3 , Chiara Bellio 1 , Stefano Indraccolo 2, * , Alberto Amadori 1, 2, * 1 Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy 2 Istituto Oncologico Veneto IRCCS, Padova, Italy 3 Laboratory of Molecular Pharmacology, Oncology Department, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy * These authors contributed equally to this work Correspondence to: Stefano Indraccolo, email: stefano.indraccolo@unipd.it Anna Pasto, email: annapasto.phd@gmail.com Keywords: glucose addiction, platinum resistance, ovarian cancer, metabolism, autophagy Received: August 31, 2016      Accepted: December 15, 2016      Published: December 23, 2016 ABSTRACT 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 naive 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.