Identification of the metabolic alterations associated with the multidrug resistant phenotype in cancer and their intercellular transfer mediated by extracellular vesicles
2017
Authors:
Lopes-Rodrigues, VanessaDi Luca, Alessio
Mleczko, Justyna
Meleady, Paula
Henry, Michael
Pešić, Milica
Cabrera, Diana
van Liempd, Sebastiaan
Lima, Raquel T.
O’Connor, Robert
Falcon-Perez, Juan M.
Vasconcelos, M. Helena
Document Type:
Article (Published version)
Metadata
Show full item recordAbstract:
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.
Funding / projects:
- NORTE-01-0145-FEDER-000029
- POCI-01-0145-FEDER-007274
- ERDF (FEDER)
- SFRH/BD/87646/2012
- FRH/BPD/68787/2010
- ME-HaD, BM1202
- ECOST-STSM-BM1202-180216-071544
In:
- Scientific Reports (2017), 7: 44541
DOI: 10.1038/srep44541
ISSN: 2045-2322
PubMed: 28303926