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

Abstract

The human multidrug-resistance (MDR1) P-glycoprotein (Pgp) is an ATP-binding-cassette transporter (ABCB1) that is ubiquitously expressed. Often its concentration is high in the plasma membrane of cancer cells, where it causes multidrug resistance by pumping lipophilic drugs out of the cell. In addition, MDR1 Pgp can transport analogues of membrane lipids with shortened acyl chains across the plasma membrane. We studied a role for MDR1 Pgp in transport to the cell surface of the signal-transduction molecule platelet-activating factor (PAF). PAF is the natural short-chain phospholipid 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. [(14)C]PAF synthesized intracellularly from exogenous alkylacetylglycerol and [(14)C]choline became accessible to albumin in the extracellular medium of pig kidney epithelial LLC-PK1 cells in the absence of vesicular transport. Its translocation across the apical membrane was greatly stimulated by the expression of MDR1 Pgp, and inhibited by the MDR1 inhibitors PSC833 and cyclosporin A. Basolateral translocation was not stimulated by expression of the basolateral drug transporter MRP1 (ABCC1). It was insensitive to the MRP1 inhibitor indomethacin and to depletion of GSH which is required for MRP1 activity. While efficient transport of PAF across the apical plasma membrane may be physiologically relevant in MDR1-expressing epithelia, PAF secretion in multidrug-resistant tumours may stimulate angiogenesis and thereby tumour growth.

The ABC of dendritic cell development and function

“…Although never fully elucidated, possible P-gp substrates responsible for this effect on migration could include PAF or S1P (Table II) [8,23]. The same group later reported MRP1 expression on both mouse and human DCs, with considerably higher expression levels in mice, and showed that DC migration was hampered in mice lacking Mrp1 expression [7].…”

“…Several ABC transporters have been recognized for their roles in generating clinical multidrug resistance of tumor cells owing to their ability to remove various cytostatic drugs from tumor cells ( Figure Ia), thereby reducing the intracellular drug load and preventing tumor cell killing [1,3,4]. ABC transporters are expressed on immune cells such as DCs and immune regulatory molecules have been identified as physiological ABC transporter substrates [6,7,9,10,23,25,26,69], which prompted a model whereby substrate secretion can result in autocrine or paracrine induction of intracellular signaling, leading to cell differentiation and migration ( Figure Ib) [12]. Polymorphisms have been reported in ABC transporter genes, which could affect their substrate specificity [70].…”

“…In recent years data have also accumulated on the expression and physiological relevance of ABC transporters in immune cells [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] (their expression on hematopoietic cells was recently reviewed by Kock et al [22]). Apart from an obvious protective function related to their capacity to extrude toxic compounds, the finding that various small inflammatory mediators such as prostaglandins, leukotrienes and cyclic nucleotides are among the natural substrates of ABC transporters strongly suggests additional regulatory functions of these pumps in immune cells [23][24][25][26] (see Figure Ib in Box 1). Although expression of these transporters on immune cells has not yet been linked to specific physiological functions in all cases, recent reports do provide evidence of the involvement of these pumps in the development and functionality of T-cells and dendritic cells (DCs) and have implicated them in processes as diverse as T-cell activation, cytokine secretion and DC migration [8][9][10]15,16,27].…”

Lipid flippases and their biological functions

“…First hints for a role of some family members in 2914 T. Pomorski and A. K. Menon Lipid flippases and their biological functions the outward movement of lipids across the PM came from the finding that PC secretion into mouse bile required ABCB4 [108] and that this liver transporter enhanced transport of newly synthesized PC to the surface of transgenic fibroblasts [109]. In studies on short chain lipids, human ABCB4 was found to be specific for PC, whereas, unexpectedly, the closely related multidrug transporter ABCB1 translocated a wide variety of short chain lipids [110][111][112][113], including the short chain PC platelet-activating factor [114,115]. The glutathione-dependent multidrug transporter ABCC1 transported short-chain PC, PS, sphingomyelin, and glucosylceramide analogs and has been suggested to maintain the outward orientation of natural choline phospholipids to the PM [116][117][118][119].…”

The Human P-Glycoprotein Transporter Enhances the Type I Interferon Response to Listeria monocytogenes Infection

“…Several studies have indicated roles for P-gp in lipid transport, intracellular trafficking of cholesterol, cell death, cell differentiation, and immune responses (16,17). Regarding the last, P-gp was shown to exhibit immunomodulatory activity and to influence the secretion of various inflammatory mediators, such as steroids, prostaglandins, platelet-activating factor, and cytokines (13,(18)(19)(20)(21). Specifically, it was demonstrated that P-gp mediates the secretion of interleukin 2 (IL-2), IL-4, tumor necrosis factor alpha (TNF-␣), and gamma interferon (IFN-␥) in T lymphocytes (19,22,23) and of cytotoxic compounds in NK cells (24).…”