Gangliosides do not affect ABC transporter function in human neuroblastoma cells

Dijkhuis, Anne-Jan; Klappe, Katharina; Kamps, Willem A.; Sietsma, Hannie

doi:10.1194/jlr.m500518-jlr200

Cited by 16 publications

(12 citation statements)

References 33 publications

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“…Both MRP1 in HT29 col MDR tumour cells and Pgp in 2780AD MDR tumour cells were found to be enriched in membrane domains defined by their insolubility in the non-ionic detergent Lubrol. It was shown previously that inhibition of GCS and hence depletion of glycosphingolipids did not affect MRP1 efflux activity in HT29 col cells [39] or in human neuroblastoma cells [18]. As noted above, other sphingolipids, probably SM and Cer, can compensate for the loss of glycosphingolipids under the conditions of GCS inhibition.…”

Section: Discussionmentioning

confidence: 74%

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Extensive sphingolipid depletion does not affect lipid raft integrity or lipid raft localization and efflux function of the ABC transporter MRP1

Klappe

Dijkhuis

Hummel

et al. 2010

Biochemical Journal

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We show that highly efficient depletion of sphingolipids in two different cell lines does not abrogate the ability to isolate Lubrol-based DRMs (detergent-resistant membranes) or detergent-free lipid rafts from these cells. Compared with control, DRM/detergent-free lipid raft fractions contain equal amounts of protein, cholesterol and phospholipid, whereas the classical DRM/lipid raft markers Src, caveolin-1 and flotillin display the same gradient distribution. DRMs/detergent-free lipid rafts themselves are severely depleted of sphingolipids. The fatty acid profile of the remaining sphingolipids as well as that of the glycerophospholipids shows several differences compared with control, most prominently an increase in highly saturated C16 species. The glycerophospholipid headgroup composition is unchanged in sphingolipid-depleted cells and cell-derived detergent-free lipid rafts. Sphingolipid depletion does not alter the localization of MRP1 (multidrug-resistance-related protein 1) in DRMs/detergent-free lipid rafts or MRP1-mediated efflux of carboxyfluorescein. We conclude that extensive sphingolipid depletion does not affect lipid raft integrity in two cell lines and does not affect the function of the lipid-raft-associated protein MRP1.

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Section: Discussionmentioning

confidence: 74%

“…One study described that gangliosides activate Pgp through modulation of its phosphorylation state [17]. Another study reached the conclusion that gangliosides are not involved in modulation of ABC transporter localization and function [18]. …”

Section: Introductionmentioning

confidence: 99%

Extensive sphingolipid depletion does not affect lipid raft integrity or lipid raft localization and efflux function of the ABC transporter MRP1

Klappe

Dijkhuis

Hummel

et al. 2010

Biochemical Journal

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“…Using these compounds, glucosylceramide synthase function was dissociated from MDR (59). Moreover, it was shown that both the localization in DRMs and the eOEux function of Pgp and MRP1 were not aŠected in spite of e‹cient depletion of glycolipids in human neuroblastoma cell lines SK-N-FI and SK-N-AS, respectively (60). Taken together, glycolipids in some cells appear to modulate Pgp, but are clearly not essential as they are without eŠect in other tumor cell lines.…”

Section: F Sphingolipidsmentioning

confidence: 86%

Are lipid rafts involved in ABC transporter-mediated drug resistance of tumor cells?

Klappe

Hummel

Kroesen

et al. 2008

TIGG

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373Trends in Glycoscience and Glycotechnology Vol. 20 No. 116 (2008) AbstractSince their discovery, lipid rafts have been implicated in several cellular functions, including protein transport in polarized cells and signal transduction. Also in multidrug resistance lipid rafts may be important with regard to the localization of ATP-binding cassette (ABC) transporters in these membrane domains. This speciˆc localization may support the activity of these ABC transporters as drug eOEux pumps and this raises important questions regarding the dependence on lipid raft constituents. In this respect, two lipid classes immediately come into play, as both sphingolipids and sterols are generally assumed to be important in the generation and maintenance of lipid rafts. Apart from lateral interactions with lipids in the membrane bilayer, one can also envision that transverse interactions with respect to the membrane bilayer play a role in positioning and function of ABC transporters. Indeed, some evidence exists for a role of the actin cytoskeleton in stabilizing the position of ABC transporters in a certain membrane area. ABC transporters may be directly linked to the actin cytoskeleton, or indirectly via lipid rafts. In this review, we will evaluate whether ABC transporters are dependent on a particular membrane environment for their function and which of the lipid raft constituents appear to be essential for this dependency.

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“…The MDR phenotype of cells used in this work is well described, being representative of freshly obtained cells from patients with chemotherapy refractory chronic myeloid leukemia (42,43). In spite of data indicating that GlcCer modulates ABCB1 expression (17), and considering the promiscuity and overlap in recognition of substrates (44), the relevance of GSL to ABC activity is controversial at best (45). As such, we observed that sub-toxic GSL depletion was not able to affect the expression of ABCB1 and ABCC1 on neither MDR cell; a 24 h incubation with 2 M EtDO-P4, however, showed reductions in the expression of ABCB1 exclusively.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differential modulation of ABC transporters on chronic myeloid leukemias

Salustiano

Costa

Freire-de-Lima

et al. 2020

Preprint

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Multidrug resistance (MDR) in cancer manifests due to cross-resistance to chemotherapeutic drugs with neither structural nor functional relationship, markedly by increased expression and activity of ABC superfamily transporters. Evidences indicate sphingolipids as substrates to ABC proteins in processes such as cell signaling, membrane biosynthesis and inflammation, and products of its biosynthetic route were shown to favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key cell regulator enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Under stress, cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after assimilation into GlcCer by UGCG. Given that cancer cells seem to mobilize UGCG and increase GSL contents for the clearance of ceramides ultimately contributing to treatment failure, we studied how inhibiting GSL biosynthesis would affect the MDR phenotype of chronic myeloid leukemias. Results indicate that MDR associates to higher expression of UGCG and to a complex GSL profile. Inhibition of this glucosyltransferase greatly reduced GM1 expression, and cotreatment with standard chemotherapeutics sensitized cells leading to mitochondrial membrane potential loss and apoptosis. Despite reducing ABCB1 expression, only the ABCC-mediated efflux activity was affected. Consistently, efflux of C6-ceramide, one byproduct of UGCG downregulation, was reduced after inhibition of ABCC-mediated transport. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, overcoming drug resistance through distinct mechanisms. This work brings more comprehension about the involvement of GSL for chemotherapy failure, and modulation of its contents emerges as an intervention targeted to MDR leukemias.

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Gangliosides do not affect ABC transporter function in human neuroblastoma cells

Cited by 16 publications

References 33 publications

Extensive sphingolipid depletion does not affect lipid raft integrity or lipid raft localization and efflux function of the ABC transporter MRP1

Extensive sphingolipid depletion does not affect lipid raft integrity or lipid raft localization and efflux function of the ABC transporter MRP1

Are lipid rafts involved in ABC transporter-mediated drug resistance of tumor cells?

Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differential modulation of ABC transporters on chronic myeloid leukemias

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