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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| Format: | Article |
| Language: | English |
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MDPI AG
2024-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/16/7/1418 |
| _version_ | 1797212805677449216 |
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| author | Julieta Afonso Catarina Barbosa-Matos Ricardo Silvestre Joana Pereira-Vieira Samuel Martins Gonçalves Camille Mendes-Alves Pier Parpot Joana Pinto Ângela Carapito Paula Guedes de Pinho Lúcio Santos Adhemar Longatto-Filho Fátima Baltazar |
| author_facet | Julieta Afonso Catarina Barbosa-Matos Ricardo Silvestre Joana Pereira-Vieira Samuel Martins Gonçalves Camille Mendes-Alves Pier Parpot Joana Pinto Ângela Carapito Paula Guedes de Pinho Lúcio Santos Adhemar Longatto-Filho Fátima Baltazar |
| author_sort | Julieta Afonso |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-24T10:48:13Z |
| format | Article |
| id | doaj.art-c5a2266239644f7e8aabb54961f7db7d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-04-24T10:48:13Z |
| publishDate | 2024-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-c5a2266239644f7e8aabb54961f7db7d2024-04-12T13:16:18ZengMDPI AGCancers2072-66942024-04-01167141810.3390/cancers16071418Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg EffectJulieta Afonso0Catarina Barbosa-Matos1Ricardo Silvestre2Joana Pereira-Vieira3Samuel Martins Gonçalves4Camille Mendes-Alves5Pier Parpot6Joana Pinto7Ângela Carapito8Paula Guedes de Pinho9Lúcio Santos10Adhemar Longatto-Filho11Fátima Baltazar12Life and Health Sciences Research Institute (ICVS), Campus de Gualtar, University of Minho, 4710-057 Braga, PortugalLife and Health Sciences Research Institute (ICVS), Campus de Gualtar, University of Minho, 4710-057 Braga, PortugalLife and Health Sciences Research Institute (ICVS), Campus de Gualtar, University of Minho, 4710-057 Braga, PortugalLife and Health Sciences Research Institute (ICVS), Campus de Gualtar, University of Minho, 4710-057 Braga, PortugalLife and Health Sciences Research Institute (ICVS), Campus de Gualtar, University of Minho, 4710-057 Braga, PortugalCQUM, Centre of Chemistry, Chemistry Department, Campus de Gualtar, University of Minho, 4710-057 Braga, PortugalCQUM, Centre of Chemistry, Chemistry Department, Campus de Gualtar, University of Minho, 4710-057 Braga, PortugalAssociate Laboratory i4HB—Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, PortugalAssociate Laboratory i4HB—Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, PortugalAssociate Laboratory i4HB—Institute for Health and Bioeconomy, University of Porto, 4050-313 Porto, PortugalExperimental Pathology and Therapeutics Group, Research Center of the Portuguese Institute of Oncology (CI-IPOP), 4200-072 Porto, PortugalLife and Health Sciences Research Institute (ICVS), Campus de Gualtar, University of Minho, 4710-057 Braga, PortugalLife and Health Sciences Research Institute (ICVS), Campus de Gualtar, University of Minho, 4710-057 Braga, PortugalAdvanced 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.https://www.mdpi.com/2072-6694/16/7/1418urothelial bladder cancercisplatin resistanceWarburg effectglucoselactatelipid metabolism |
| spellingShingle | Julieta Afonso Catarina Barbosa-Matos Ricardo Silvestre Joana Pereira-Vieira Samuel Martins Gonçalves Camille Mendes-Alves Pier Parpot Joana Pinto Ângela Carapito Paula Guedes de Pinho Lúcio Santos Adhemar Longatto-Filho Fátima Baltazar Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect Cancers urothelial bladder cancer cisplatin resistance Warburg effect glucose lactate lipid metabolism |
| title | Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect |
| title_full | Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect |
| title_fullStr | Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect |
| title_full_unstemmed | Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect |
| title_short | Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect |
| title_sort | cisplatin resistant urothelial bladder cancer cells undergo metabolic reprogramming beyond the warburg effect |
| topic | urothelial bladder cancer cisplatin resistance Warburg effect glucose lactate lipid metabolism |
| url | https://www.mdpi.com/2072-6694/16/7/1418 |
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