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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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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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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers16071418</identifier><identifier>PMID: 38611096</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>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</subject><ispartof>Cancers, 2024-04, Vol.16 (7), p.1418</ispartof><rights>COPYRIGHT 2024 MDPI AG</rights><rights>2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c412t-69c11f6351715a5d083ce5c7ab43722add1b12095dda1ee5bebc81aa95989c883</cites><orcidid>0000-0003-1396-4485 ; 0000-0002-5779-9752 ; 0000-0002-9748-3752 ; 0000-0002-7395-5700 ; 0000-0003-1031-4241 ; 0000-0002-5413-3445 ; 0000-0002-9270-2717 ; 0000-0001-9719-8364 ; 0000-0002-1770-4544</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27926,27927</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38611096$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Afonso, Julieta</creatorcontrib><creatorcontrib>Barbosa-Matos, Catarina</creatorcontrib><creatorcontrib>Silvestre, Ricardo</creatorcontrib><creatorcontrib>Pereira-Vieira, Joana</creatorcontrib><creatorcontrib>Gonçalves, Samuel Martins</creatorcontrib><creatorcontrib>Mendes-Alves, Camille</creatorcontrib><creatorcontrib>Parpot, Pier</creatorcontrib><creatorcontrib>Pinto, Joana</creatorcontrib><creatorcontrib>Carapito, Ângela</creatorcontrib><creatorcontrib>Guedes de Pinho, Paula</creatorcontrib><creatorcontrib>Santos, Lúcio</creatorcontrib><creatorcontrib>Longatto-Filho, Adhemar</creatorcontrib><creatorcontrib>Baltazar, Fátima</creatorcontrib><title>Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><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.</description><subject>Acidification</subject><subject>Amino acids</subject><subject>Antibodies</subject><subject>Biomarkers</subject><subject>Biosynthesis</subject><subject>Bladder cancer</subject><subject>California</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Chemoresistance</subject><subject>Cisplatin</subject><subject>Dehydrogenases</subject><subject>Genotype & phenotype</subject><subject>Glucose</subject><subject>Glucose metabolism</subject><subject>Glutamate</subject><subject>Glycolysis</subject><subject>Health aspects</subject><subject>Japan</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Lactates</subject><subject>Lactic acid</subject><subject>Lipid metabolism</subject><subject>Massachusetts</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Medicine, Experimental</subject><subject>Metabolic pathways</subject><subject>Metabolism</subject><subject>Metabolomics</subject><subject>Metastasis</subject><subject>Missouri</subject><subject>Mitochondrial DNA</subject><subject>Mortality</subject><subject>Older people</subject><subject>Oxidative phosphorylation</subject><subject>Oxygen consumption</subject><subject>Phenotypes</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Portugal</subject><subject>Proteins</subject><subject>Scientific equipment and supplies industry</subject><subject>Tumors</subject><subject>United States</subject><subject>Urothelial 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Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-69c11f6351715a5d083ce5c7ab43722add1b12095dda1ee5bebc81aa95989c883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Acidification</topic><topic>Amino acids</topic><topic>Antibodies</topic><topic>Biomarkers</topic><topic>Biosynthesis</topic><topic>Bladder cancer</topic><topic>California</topic><topic>Cancer therapies</topic><topic>Cell cycle</topic><topic>Cell 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Joana</au><au>Carapito, Ângela</au><au>Guedes de Pinho, Paula</au><au>Santos, Lúcio</au><au>Longatto-Filho, Adhemar</au><au>Baltazar, Fátima</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2024-04-05</date><risdate>2024</risdate><volume>16</volume><issue>7</issue><spage>1418</spage><pages>1418-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>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. 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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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