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Updated: Oct 13, 2026
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Induction of P-glycoprotein expression on the plasma membrane of human melanoma cells
A Molinari1, L Toccacieli, A Calcabrini
1Laboratorio di Ultrastrutture, Istituto Superiore di Sanità, Rome, Italy. molinari@iss.it
Abstract:
Melanoma cells exhibit, both in vivo and in vitro, intrinsic drug resistance to various chemotherapeutic agents. Cultured human melanoma cells (M14) intrinsically express significant amounts of multidrug resistance-related protein (MRP1) and P-glycoprotein (P-gp) in the Golgi apparatus, but do not express these drug transporters on the plasma membrane. A panel of multidrug resistant (MDR) melanoma cell lines (M14Dx), showing different degrees of resistance to doxorubicin (DOX), were isolated. In M14Dx lines, the appearance of surface P-gp, but not of MRP1 or lung resistance related protein (LRP), occurred in cells grown in the presence of DOX concentrations higher than 60 nM. Furthermore, P-gp levels appeared to be dose-dependent. Flow cytometry, laser scanning confocal microscopy and cytotoxicity studies demonstrated that the activity of the drug extrusion system was related to both surface P-gp expression and resistance to DOX. In conclusion, P-gp, but not MRP1 or LRP, might play a pivotal role in the pharmacologically-induced MDR phenotype of melanoma cells.
Insights
Melanoma cells develop drug resistance through P-glycoprotein (P-gp) on their surface, not MRP1 or LRP. This P-gp activity is linked to doxorubicin resistance and its surface expression is dose-dependent.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Melanoma cells intrinsically resist chemotherapy.
- Human melanoma cells (M14) express multidrug resistance-related protein (MRP1) and P-glycoprotein (P-gp) in the Golgi apparatus.
- These drug transporters are not initially present on the plasma membrane.
Purpose of the Study:
- To investigate the role of drug transporters in acquired multidrug resistance (MDR) in melanoma.
- To determine the specific transporters involved in doxorubicin (DOX) resistance in melanoma cell lines.
- To understand the relationship between transporter expression and drug resistance levels.
Main Methods:
- Isolation of multidrug resistant (MDR) melanoma cell lines (M14Dx) with varying doxorubicin (DOX) resistance.
- Analysis of drug transporter expression (MRP1, P-gp, LRP) on the cell surface using flow cytometry and laser scanning confocal microscopy.
- Cytotoxicity studies to assess drug resistance and its correlation with transporter activity.
Main Results:
- Acquired doxorubicin (DOX) resistance in M14Dx cell lines was associated with the appearance of P-glycoprotein (P-gp) on the cell surface.
- Surface P-gp expression was observed at DOX concentrations above 60 nM and was dose-dependent.
- Neither MRP1 nor lung resistance related protein (LRP) were found on the cell surface in resistant lines.
- The activity of the drug extrusion system correlated with both surface P-gp levels and DOX resistance.
Conclusions:
- P-glycoprotein (P-gp) plays a significant role in the development of pharmacologically-induced multidrug resistance (MDR) in melanoma cells.
- MRP1 and LRP do not appear to be major contributors to this acquired MDR phenotype in the studied melanoma models.
- Targeting surface P-gp may be a potential strategy to overcome doxorubicin resistance in melanoma.
