Advanced urothelial bladder cancer (UBC) patients are tagged by a dismal prognosis and high mortality rates, mostly due to their poor response to standard-of-care platinum-based therapy. Mediators of chemoresistance are not fully elucidated. This work aimed to study the metabolic profile of advanced UBC, in the context of cisplatin resistance. Three isogenic pairs of parental cell lines (T24, HT1376 and KU1919) and the matching cisplatin-resistant (R) sublines were used. A set of functional assays was used to perform a metabolic screening on the cells. In comparison to the parental sublines, a tendency was observed towards an exacerbated glycolytic metabolism in the cisplatin-resistant T24 and HT1376 cells; this glycolytic phenotype was particularly evident for the HT1376/HT1376R pair, for which the cisplatin resistance ratio was higher. HT1376R cells showed decreased basal respiration and oxygen consumption associated with ATP production; in accordance, the extracellular acidification rate was also higher in the resistant subline. Glycolytic rate assay confirmed that these cells presented higher basal glycolysis, with an increase in proton efflux. While the results of real-time metabolomics seem to substantiate the manifestation of the Warburg phenotype in HT1376R cells, a shift towards distinct metabolic pathways involving lactate uptake, lipid biosynthesis and glutamate metabolism occurred with time. On the other hand, KU1919R cells seem to engage in a metabolic rewiring, recovering their preference for oxidative phosphorylation. In conclusion, cisplatin-resistant UBC cells seem to display deep metabolic alterations surpassing the Warburg effect, which likely depend on the molecular signature of each cell line.
晚期尿路上皮膀胱癌（UBC）患者预后极差且死亡率高，这主要归因于其对标准铂类化疗方案反应不佳。目前，化疗耐药的具体机制尚未完全阐明。本研究旨在探讨顺铂耐药背景下晚期UBC的代谢特征。研究采用三对同源亲本细胞系（T24、HT1376和KU1919）及其对应的顺铂耐药（R）亚系，通过一系列功能实验对细胞进行代谢筛查。与亲本亚系相比，顺铂耐药的T24和HT1376细胞显示出糖酵解代谢增强的趋势；这一糖酵解表型在HT1376/HT1376R细胞对中尤为明显，该细胞对的顺铂耐药比也更高。HT1376R细胞的基础呼吸和与ATP产生相关的耗氧量降低；相应地，耐药亚系的细胞外酸化率也更高。糖酵解速率测定证实这些细胞具有更高的基础糖酵解水平，质子外流增加。实时代谢组学结果似乎证实了HT1376R细胞中Warburg表型的表现，但随时间推移，这些细胞转向了涉及乳酸摄取、脂质生物合成和谷氨酸代谢的独特代谢途径。另一方面，KU1919R细胞似乎发生了代谢重编程，恢复了其对氧化磷酸化的偏好。总之，顺铂耐药的UBC细胞表现出超越Warburg效应的深度代谢改变，这些改变可能取决于各细胞系的分子特征。
肿瘤(癌症)患者之家