Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect

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...

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Veröffentlicht in:Cancers 2024-04, Vol.16 (7), p.1418
Hauptverfasser: Afonso, Julieta, Barbosa-Matos, Catarina, Silvestre, Ricardo, Pereira-Vieira, Joana, Gonçalves, Samuel Martins, Mendes-Alves, Camille, Parpot, Pier, Pinto, Joana, Carapito, Ângela, Guedes de Pinho, Paula, Santos, Lúcio, Longatto-Filho, Adhemar, Baltazar, Fátima
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container_end_page
container_issue 7
container_start_page 1418
container_title Cancers
container_volume 16
creator Afonso, Julieta
Barbosa-Matos, Catarina
Silvestre, Ricardo
Pereira-Vieira, Joana
Gonçalves, Samuel Martins
Mendes-Alves, Camille
Parpot, Pier
Pinto, Joana
Carapito, Ângela
Guedes de Pinho, Paula
Santos, Lúcio
Longatto-Filho, Adhemar
Baltazar, Fátima
description 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.
doi_str_mv 10.3390/cancers16071418
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source MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central; EZB Electronic Journals Library; PubMed Central Open Access
subjects Acidification
Amino acids
Antibodies
Biomarkers
Biosynthesis
Bladder cancer
California
Cancer therapies
Cell cycle
Cell growth
Chemoresistance
Cisplatin
Dehydrogenases
Genotype & phenotype
Glucose
Glucose metabolism
Glutamate
Glycolysis
Health aspects
Japan
Kinases
Laboratories
Lactates
Lactic acid
Lipid metabolism
Massachusetts
Medical prognosis
Medical research
Medicine, Experimental
Metabolic pathways
Metabolism
Metabolomics
Metastasis
Missouri
Mitochondrial DNA
Mortality
Older people
Oxidative phosphorylation
Oxygen consumption
Phenotypes
Phosphorylation
Physiological aspects
Portugal
Proteins
Scientific equipment and supplies industry
Tumors
United States
Urothelial cancer
title Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect
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