Pastò Anna, Pagotto Anna, Pilotto Giorgia, De Paoli Angela, De Salvo Gian Luca, Baldoni Alessandra, Nicoletto Maria Ornella, Ricci Francesca, Damia Giovanna, Bellio Chiara, Indraccolo Stefano, Amadori Alberto
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
Istituto Oncologico Veneto IRCCS, Padova, Italy.
Oncotarget. 2017 Jan 24;8(4):6433-6445. doi: 10.18632/oncotarget.14118.
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.
在癌症中观察到葡萄糖代谢失调，但这种代谢特征是否影响细胞毒性药物的反应或受其调节尚不清楚。我们在此表明，上皮性卵巢癌（EOC）患者的肿瘤细胞可根据其在葡萄糖饥饿条件下的体外活力，分为葡萄糖剥夺敏感型（葡萄糖成瘾型，GA）和葡萄糖剥夺抵抗型（葡萄糖非成瘾型，GNA）。当EOC细胞在无葡萄糖条件下培养时，铂类（PLT）敏感患者的所有样本均属于GA组；它们表现出更高的葡萄糖代谢酶表达、更高的增殖率以及对PLT的体外敏感性。此外，与GNA样本相比，GA患者的多药耐药泵表达和自噬减少。在异种移植模型中证实了PLT敏感性与葡萄糖代谢谱之间的密切关联，在该模型中确定了PLT敏感性/抗性与葡萄糖代谢之间的严格平行关系。最后，在一组初治EOC患者中，诊断时分为GA或GNA，Kaplan Meier曲线显示，与GNA患者相比，GA表型与显著更好的无进展生存期相关。
