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Altered plasma membrane ultrastructure in multidrug-resistant cells
A L Arsenault1, V Ling, N Kartner
1Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
Abstract:
Multidrug resistance is mediated by P-glycoprotein, an integral plasma membrane component which is thought to function as a drug export pump. This model can explain drug resistance, but fails to account for the broader pleiotropy of the multidrug resistance phenotype. We report here a freeze-fracture study revealing increases in the densities of protoplasmic face intramembrane particles in multidrug-resistant Chinese hamster ovary (CHO) and human leukemic cells. The intramembrane particle density in a CHO cell revertant which had lost the characteristics of the multidrug resistance phenotype was indistinguishable from that of the drug-sensitive parental cell line. This demonstration of a global multidrug resistance-linked change in plasma membrane architecture may have significant implications for understanding the variety of concurrent membrane-related changes which are not easily explained by the current model for multidrug resistance.
Insights
Multidrug resistance in cancer cells involves changes in plasma membrane structure, not just P-glycoprotein pumps. Freeze-fracture studies reveal increased particle density in resistant cells, suggesting altered membrane architecture.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Multidrug resistance (MDR) is a major challenge in cancer therapy.
- P-glycoprotein (P-gp) is a known mediator of MDR, acting as a drug efflux pump.
- The current P-gp model does not fully explain the pleiotropic nature of MDR.
Purpose of the Study:
- To investigate the structural changes in the plasma membrane associated with multidrug resistance.
- To determine if MDR induces global alterations in membrane architecture beyond P-gp function.
Main Methods:
- Utilized freeze-fracture electron microscopy to analyze plasma membrane structure.
- Compared membrane intramembrane particle (IMP) densities in drug-resistant and drug-sensitive cell lines.
- Examined IMP densities in a revertant cell line that lost MDR characteristics.
Main Results:
- Multidrug-resistant Chinese hamster ovary (CHO) and human leukemic cells showed increased IMP densities.
- A revertant CHO cell line, which lost its MDR phenotype, exhibited IMP densities similar to drug-sensitive cells.
- These findings indicate a correlation between MDR and altered plasma membrane architecture.
Conclusions:
- MDR is associated with significant changes in plasma membrane structure, specifically increased IMP density.
- These structural alterations suggest a broader role for membrane architecture in the MDR phenotype.
- The findings challenge the sole reliance on the P-gp efflux pump model and highlight the importance of membrane dynamics in MDR.