Role of Multiple Drug Resistance Protein 1 in Neutral but Not Acidic Glycosphingolipid Biosynthesis

Rosa, María Fabiana De; Sillence, Daniel J.; Ackerley, Cameron; Lingwood, Clifford A.

doi:10.1074/jbc.m305645200

Cited by 109 publications

(116 citation statements)

References 73 publications

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“…It has been suggested that the multiple drug resistance pump, MDR1, is the GlcCer flippase in the Golgi apparatus, but other proteins might also be involved. However, inhibition of MDR1 by cyclosporin A inhibits LacCer and globotriaosyl ceramide synthesis, but not ganglioside synthesis [59]. This suggests that neutral and acid GSLs are synthesized from distinct precursor GSL pools.…”

Section: Glccer Synthase (Gcs) (Reaction X)mentioning

confidence: 98%

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The ins and outs of sphingolipid synthesis

Futerman

Riezman

2005

Trends in Cell Biology

304

266

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Section: Glccer Synthase (Gcs) (Reaction X)mentioning

confidence: 98%

“…There is some controversy about the molecular identification of the flippase responsible for transbilayer movement of GlcCer [59]. It has been suggested that the multiple drug resistance pump, MDR1, is the GlcCer flippase in the Golgi apparatus, but other proteins might also be involved.…”

Section: Glccer Synthase (Gcs) (Reaction X)mentioning

confidence: 99%

The ins and outs of sphingolipid synthesis

Futerman

Riezman

2005

Trends in Cell Biology

304

266

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“…Glucosylceramide synthesized on the cytosolic surface of the cis-Golgi, which utilizes a different pool of ceramide, spontaneously translocates across the membrane to be converted to lactosylceramide and the ganglioside GM3. Translocation to the lumen of the trans-Golgi via the ABC transporter MDR1 may be specific for a glucosylceramide pool destined for the synthesis of neutral glycolipids [42]. PM, plasma membrane.…”

Section: Sphingolipid/cholesterol Domains and Sortingmentioning

confidence: 99%

Membrane lipids and vesicular traffic

Meer

Sprong

2004

Current Opinion in Cell Biology

159

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Lipids were long considered to be passive passengers of carrier vesicles with the single role of sealing the transport container. We now know that specific phospholipids are required for efficient fusion, while others facilitate budding and fission. Moreover, the various polyphosphoinositides assist in the recruitment from the cytosol of proteins of the transport machinery. Finally, the segregation of membrane lipids into different fluid phases appears to serve as a 'lipid raft' mechanism for protein sorting at various stages of the secretory and endocytic pathways. The current challenge is to understand how proteins control the metabolism and subcellular localization, and thereby the activity, of the various lipids.

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“…Subsequent study showed that structurally diverse P-gp antagonists such as tamoxifen, verapamil, and cyclosporin A, inhibited GC synthesis in multidrug-resistant cancer cells (19). This observation was supported by De Rosa et al (20) in a study using cyclosporin A and ketoconazole in P-gp-containing cell lines. Furthermore, the study of Shabbits and Mayer (21) demonstrated that P-gp can modulate cellular sensitivity to endogenously generated longchain ceramide in response to taxane exposure.…”

Section: Introductionmentioning

confidence: 80%

Expression of P-glycoprotein in HeLa cells confers resistance to ceramide cytotoxicity

Chapman

Gouazé-Andersson²,

Cabot³

2010

Int J Oncol

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Abstract. The role of glucosylceramide synthase (GCS) in regulating ceramide-induced apoptosis has been widely studied. The purpose of this investigation was to evaluate the role of P-glycoprotein (P-gp) in regulating ceramide cytotoxicity by using C 6 -ceramide. To accomplish this, we employed HeLa cells with conditional expression of the multidrug resistance gene 1/P-gp. HeLa cells expressing P-gp (P-gp/on cells) challenged with [14 C]C 6 -ceramide (6 μM), synthesized 4.5-fold the amount of C 6 -glucosylceramide (GC) compared to HeLa cells with suppressed expression of P-gp (P-gp/off cells), whereas the generated levels of C 6 -sphingomyelin were almost equal (33 and 29% of intracellular 14 C, respectively). Tamoxifen, a P-gp antagonist, decreased the C 6 -GC levels from 3.5-1.0% in the P-gp/off and from 17-2.8% of the total lipid 14 C levels in the P-gp/on cells. Tamoxifen did not inhibit cell-free C 6 -GC synthesis in the P-gp/off or P-gp/on homogenates. However, a specific GCS inhibitor, ethylenedioxy-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (ethylenedioxy-P4), blocked synthesis by 90%. In the cytotoxicity assays, the P-gp/off cells were sensitive to C 6 -ceramide and the P-gp/on cells were resistant. Resistance to C 6 -ceramide in the P-gp/on cells was reversed by tamoxifen but not by ethylenedioxy-P4. Experiments in another cervical cancer model showed that multidrug-resistant P-gp-rich KB-V1 cells synthesized 3-fold more C 6 -GC from C 6 -ceramide than the parental, P-gp-poor KB-3-1 cells, and whereas tamoxifen had no effect on the C 6 -GC synthesis in the KB-3-1 cells, it inhibited synthesis by 70% in the KB-V1 cells. This study demonstrates that P-gp potentiates C 6 -ceramide glycosylation and if antagonized augments C 6 -ceramide sensitivity, both features previously ascribed to GCS. We propose that P-gp can be an effective target for enhancing short-chain ceramide cytotoxicity in the treatment of drug-resistant cancer.

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Role of Multiple Drug Resistance Protein 1 in Neutral but Not Acidic Glycosphingolipid Biosynthesis

Cited by 109 publications

References 73 publications

The ins and outs of sphingolipid synthesis

The ins and outs of sphingolipid synthesis

Membrane lipids and vesicular traffic

Expression of P-glycoprotein in HeLa cells confers resistance to ceramide cytotoxicity

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