Identification of the metabolic alterations associated with the multidrug resistant phenotype
in cancer and their intercellular transfer mediated by extracellular vesicles

Cancer multidrug resistance (MDR) is a major cause of therapeutic failure in cancer. MDR is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). Besides overexpression of drug efflux pumps, other molecular mechanisms are involved in the MDR phenotype, including metabolic alterations. Indeed, recent studies showed that it is possible to revert the MDR phenotype by inhibition of glycolysis with specific modulators. Additionally, several studies have highlighted the relevance of Extracellular Vesicles (EVs) in metabolism, showing that metabolic alterations could affect the shedding and cargo of EVs released by cells.

This work shows that MDR (P-gp overexpressing) cells have a different metabolic profile from the drug-sensitive counterpart cells, exhibiting: (i) a decrease in the pentose phosphate pathway and in the oxidative phosphorylation rate; (ii) an increase in the glycolysis rate and in the methylation index; (iii) alterations in the glutathione metabolism and in the methionine/S-adenosylmethionine pathway. Additionally, the EVs, from MDR cells, were capable of causing a metabolic switch in the drug-sensitive cancer cells, towards a MDR phenotype.

Overall, this work contributed to the growing knowledge on metabolic alterations in MDR cells and on the role of a specific population of EVs in the intercellular transfer of MDR. The specific metabolic alterations identified in this study may be further developed as targets for overcoming cancer MDR.

Authors and Affiliations:

Vanessa Lopes-Rodrigues^1,2,3, Alessio Di Luca⁴, Justyna Mleczko⁵, Paula Meleady⁴, Michael Henry⁴, Milica Pesic⁶, Diana Cabrera⁵, Sebastiaan van Liempd⁵, Raquel T. Lima^1,2,7, Robert O’Connor⁴, Juan M. Falcon-Perez^5,8 & M. Helena Vasconcelos^1,2,9

¹ i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal;

² Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, IPATIMUP, 4200-465 Porto, Portugal;

³ ICBAS-UP - Institute of Biomedical Sciences Abel Salazar, University of Porto, ICBAS-UP, 4099-003 Porto, Portugal;  

⁴ NICB - National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.

⁵ Exosomes Laboratory &Metabolomics platform, CIC bioGUNE, CIBERehd, Derio, Spain

⁶ Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia.

⁷ Department of Pathology and Oncology, FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal;

⁸ IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain

⁹ Department of Biological Sciences, FFUP - Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.

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.

Journal: Scientific Reports

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356019/