title: Identification of the metabolic alterations associated with the multidrug resistant phenotype in cancer and their intercellular transfer mediated by extracellular vesicles.
abstract: Multidrug resistance (MDR) is a serious obstacle to efficient cancer treatment. Overexpression of P-glycoprotein (P-gp) plays a significant role in MDR. Recent studies proved that targeting cellular metabolism could sensitize MDR cells. In addition, metabolic alterations could affect the extracellular vesicles (EVs) cargo and release. This study aimed to: i) identify metabolic alterations in P-gp overexpressing cells that could be involved in the development of MDR and, ii) identify a potential role for the EVs in the acquisition of the MDR. Two different pairs of MDR and their drug-sensitive counterpart cancer cell lines were used. Our results showed that MDR (P-gp overexpressing) cells have a different metabolic profile from their drug-sensitive counterparts, demonstrating decreases in the pentose phosphate pathway and oxidative phosphorylation rate; increases in glutathione metabolism and glycolysis; and alterations in the methionine/S-adenosylmethionine pathway. Remarkably, EVs from MDR cells were capable of stimulating a metabolic switch in the drug-sensitive cancer cells, towards a MDR phenotype. In conclusion, obtained results contribute to the growing knowledge about metabolic alterations in MDR cells and the role of EVs in the intercellular transfer of MDR. The specific metabolic alterations identified in this study may be further developed as targets for overcoming MDR.
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal.|ICBAS-UP - Institute of Biomedical Sciences Abel Salazar, University of Porto, 4099-003 Porto, Portugal.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Lopes-Rodrigues
authors.affiliation: NICB - National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
authors.forename: Alessio
authors.initials: A
authors.lastname: Di Luca
authors.affiliation: Exosomes Laboratory &Metabolomics platform, CIC bioGUNE, CIBERehd, Derio, Spain.
authors.forename: Justyna
authors.initials: J
authors.lastname: Mleczko
authors.affiliation: NICB - National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
authors.forename: Paula
authors.initials: P
authors.lastname: Meleady
authors.affiliation: NICB - National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Henry
authors.affiliation: Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Pesic
authors.affiliation: Exosomes Laboratory &Metabolomics platform, CIC bioGUNE, CIBERehd, Derio, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Cabrera
authors.affiliation: Exosomes Laboratory &Metabolomics platform, CIC bioGUNE, CIBERehd, Derio, Spain.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: van Liempd
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal.|Department of Pathology - FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
authors.forename: Raquel T
authors.initials: RT
authors.lastname: Lima
authors.affiliation: NICB - National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
authors.forename: Robert
authors.initials: R
authors.lastname: O'Connor
authors.affiliation: Exosomes Laboratory &Metabolomics platform, CIC bioGUNE, CIBERehd, Derio, Spain.|IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Falcon-Perez
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.|Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal.|Department of Biological Sciences, FFUP - Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
authors.forename: M Helena
authors.initials: MH
authors.lastname: Vasconcelos
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D000067128:Extracellular Vesicles / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D008715:Methionine / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012436:S-Adenosylmethionine / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D012436:S-Adenosylmethionine; D008715:Methionine