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Related Experiment Videos

Multidrug-resistance P-glycoprotein (MDR1) secretes platelet-activating factor.

R J Raggers1, I Vogels, G van Meer

  • 1Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.

The Biochemical Journal
|July 21, 2001
PubMed
Summary

The multidrug-resistance P-glycoprotein (MDR1 Pgp) transports platelet-activating factor (PAF) across cell membranes. This MDR1 Pgp-mediated PAF secretion may promote tumor growth by stimulating angiogenesis.

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Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • The human multidrug-resistance P-glycoprotein (MDR1 Pgp), an ATP-binding-cassette transporter (ABCB1), is highly expressed in cancer cells, conferring multidrug resistance by effluxing lipophilic drugs.
  • MDR1 Pgp also transports membrane lipid analogues with short acyl chains, suggesting a broader role in cellular transport.

Purpose of the Study:

  • To investigate the role of MDR1 Pgp in the transport of platelet-activating factor (PAF), a signaling molecule and natural short-chain phospholipid, to the cell surface.
  • To determine if MDR1 Pgp mediates the apical secretion of PAF in epithelial cells and to compare this with the activity of other transporters like MRP1.

Main Methods:

  • Synthesized [(14)C]PAF intracellularly in LLC-PK1 cells expressing MDR1 Pgp from exogenous alkylacetylglycerol and [(14)C]choline.

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  • Assessed extracellular accessibility of [(14)C]PAF to albumin, indicating translocation across the plasma membrane.
  • Utilized MDR1 inhibitors (PSC833, cyclosporin A) and an MRP1 inhibitor (indomethacin) to evaluate transporter specificity.
  • Investigated the effect of glutathione (GSH) depletion on MRP1-mediated transport.

    • Main Results:

    • MDR1 Pgp expression significantly stimulated the translocation of [(14)C]PAF across the apical membrane of LLC-PK1 cells.
    • This MDR1 Pgp-mediated PAF translocation was inhibited by PSC833 and cyclosporin A.
    • Basolateral translocation of PAF was not enhanced by the expression of the multidrug-resistance-associated protein 1 (MRP1/ABCC1) and was insensitive to MRP1 inhibition.

    Conclusions:

    • MDR1 Pgycoprotein actively transports platelet-activating factor (PAF) across the apical plasma membrane of epithelial cells.
    • This transport mechanism is distinct from MRP1-mediated transport and may have physiological relevance in epithelia.
    • PAF secretion mediated by MDR1 Pgp in multidrug-resistant tumors could potentially promote angiogenesis and tumor progression.