Multidrug resistance protein 1 localization in lipid raft domains and prostasomes in prostate cancer cell lines

Abstract

BackgroundOne of the problems in prostate cancer (CaP) treatment is the appearance of the multidrug resistance phenotype, in which ATP-binding cassette transporters such as multidrug resistance protein 1 (MRP1) play a role. Different localizations of the transporter have been reported, some of them related to the chemoresistant phenotype.AimThis study aimed to compare the localization of MRP1 in three prostate cell lines (normal, androgen-sensitive, and androgen-independent) in order to understand its possible role in CaP chemoresistance.MethodsMRP1 and caveolae protein markers were detected using confocal microscopy, performing colocalization techniques. Lipid raft isolation made it possible to detect these proteins by Western blot analysis. Caveolae and prostasomes were identified by electron microscopy.ResultsWe show that MRP1 is found in lipid raft fractions of tumor cells and that the number of caveolae increases with malignancy acquisition. MRP1 is found not only in the plasma membrane associated with lipid rafts but also in cytoplasmic accumulations colocalizing with the prostasome markers Caveolin-1 and CD59, suggesting that in CaP cells, MRP1 is localized in prostasomes.ConclusionWe hypothesize that the presence of MRP1 in prostasomes could serve as a reservoir of MRP1; thus, taking advantage of the release of their content, MRP1 could be translocated to the plasma membrane contributing to the chemoresistant phenotype. The presence of MRP1 in prostasomes could serve as a predictor of malignancy in CaP.

Inhibition of the Lysophosphatidylinositol Transporter ABCC1 Reduces Prostate Cancer Cell Growth and Sensitizes to Chemotherapy

“…It is also worth mentioning that ABCC1 inhibition would reduce GPR55 activation and we reported previously that inhibition of this receptor potentiates the efficacy of chemotherapy [40]. Intriguingly, data in the literature also suggest that intracellular localization rather than expression of ABCC1 might be crucial for its role in prostate cancer cells [45]. In particular, the transporter was found to be localized specifically in lipid rafts and prostasomes in PC3 and LNCaP but not in PNT2 cells.…”

Prostasomas: búsqueda de biomarcadores para la detección temprana del cáncer prostático

“…En otro estudio realizado en tres líneas celulares de próstata (normal, andrógenosensible y andrógeno-independiente) derivadas de metástasis a ganglios linfáticos y hueso, respectivamente, con el fin de comprender su posible papel en la quimiorresistencia al CaP, se muestra que la proteína de resistencia Multirresistente 1 (MRP1) se encuentra en fracciones de balsa lipídica de células tumorales y que el número de caveolas aumenta con la adquisición de malignidad. MRP1 no solo se encontró en la membrana plasmática asociada con las balsas lipídicas sino también en las acumulaciones citoplásmicas que se localizan con los marcadores de prostasoma Caveolin-1 y CD59 [53]. Debido a que las tres líneas celulares mostraron prostasomas y que existe presencia de MRP1 en estos, los prostasomas podrían servir como un predictor de malignidad en CaP.…”

“…Además, se llegó a la conclusión que tal vez haya dos poblaciones diferentes de células, aquellas menos agresivas que no expresa MRP1 en prostasomas y aquellas que tienen MRP1 en prostasomas localizado siendo estas más agresivas. Se puede concluir que tanto CD59 como Cav-1 podrían actuar como marcadores de prostasoma cuando las células adquieren malignidad y que las células cancerosas que tienen más prostasomas tendrían menos MRP1 en la membrana plasmática [53].…”

Small and Innovative Molecules as New Strategy to Revert MDR

“…Some of these transporters are involved in multidrug resistance (MDR) such as ABC-B1 (P-glycoprotein, P-gp), ABC-G2 (breast cancer resistance protein, BCRP), and ABC-C1-6 (MDR associated proteins, MRP1-6) ( 3 ).…”

“…P-glycoprotein is a 170-kDa phosphorylated glycoprotein encoded by MDR1 gene. Structurally, P-gp contains 12 transmembrane helices organized in 2 membrane spanning domains (MSDs), each containing 6 transmembrane helices and 2 nucleotide-binding domains (NBDs) responsible for ATP binding ( 3 , 8 ) (Figure 1 ).…”