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Regulation of [Ca(2+)](i) homeostasis in MRP1 overexpressing cells
C M Filipeanu1, A Nelemans, R J Veldman
1Groningen University Institute for Drug Exploration, Department of Clinical Pharmacology, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Abstract:
Regulation of capacitative Ca(2+) entry was studied in two different multidrug resistance (MDR) protein (MRP1) overexpressing cell lines, HT29(col) and GLC4/ADR. MRP1 overexpression was accompanied by a decreased response to thapsigargin. Moreover, inhibition of capacitative Ca(2+) entry by D, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) was abolished in MRP1 overexpressing cells. Both PDMP and the MRP1 inhibitor MK571 greatly reduced InsP(3)-mediated (45)Ca(2+) release from intracellular stores in HT29 cells. Again, these effects were virtually abolished in HT29(col) cells. Our results point to a modulatory role of MRP1 on intracellular calcium concentration ([Ca(2+)](i)) homeostasis which may contribute to the MDR phenotype.
Insights
Multidrug resistance protein 1 (MRP1) modulates intracellular calcium. MRP1 overexpression affects calcium entry and release, potentially contributing to the multidrug resistance phenotype.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer therapy.
- Multidrug resistance protein 1 (MRP1) is a key transporter implicated in MDR.
- Intracellular calcium ([Ca2+]i) homeostasis plays a crucial role in cellular functions.
Purpose of the Study:
- To investigate the role of MRP1 in regulating capacitative calcium entry.
- To determine the effect of MRP1 overexpression on intracellular calcium handling.
- To explore the relationship between MRP1 and the MDR phenotype concerning calcium regulation.
Main Methods:
- Studied two MRP1-overexpressing cell lines: HT29(col) and GLC4/ADR.
- Assessed the response to thapsigargin, an inhibitor of the sarco/endoplasmic reticulum Ca2+-ATPase.
- Investigated the effects of D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and MRP1 inhibitor MK571 on calcium release.
Main Results:
- MRP1 overexpression led to a decreased response to thapsigargin.
- Inhibition of capacitative calcium entry by PDMP was abolished in MRP1-overexpressing cells.
- PDMP and MK571 reduced InsP3-mediated calcium release from intracellular stores in parental HT29 cells, but these effects were diminished in MRP1-overexpressing cells.
Conclusions:
- MRP1 appears to modulate intracellular calcium concentration ([Ca2+]i) homeostasis.
- This modulation of calcium homeostasis by MRP1 may contribute to the development of the MDR phenotype.
- Targeting MRP1 could offer novel strategies for overcoming multidrug resistance.