P-glycoprotein is implicated in the inhibition of ceramide-induced apoptosis in TF-1 acute myeloid leukemia cells by modulation of the glucosylceramide synthase pathway

Turzanski, J.; Grundy, Martin; Shang, Shilli; Russell, Nigel H.; Pallis, Monica

doi:10.1016/j.exphem.2004.10.005

Cited by 46 publications

(25 citation statements)

References 60 publications

(81 reference statements)

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“…In such a fashion, newly synthesized GC can be removed from GCS in conveyor-belt fashion. These ideas are supported by previous studies employing adriamycinresistant cancer cells and MDR1 gene-transfected cancer cells (21) and by studies on acute myeloid leukemia (48). However, Halter et al (47) have demonstrated that newly synthesized GC enters 2 pathways, and that natural GC and the shortchain analogs exhibit dissimilar transport.…”

Section: Discussionsupporting

confidence: 67%

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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Section: Discussionsupporting

confidence: 67%

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

Chapman

Gouazé-Andersson²,

Cabot³

2010

Int J Oncol

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“…From here, GlcCer can reach the plasma membrane by direct transport, or it can be modified by further glycosylation in the Golgi apparatus [37, 50,51]. Glucose is first glycosylated with the C1 hydroxyl group of ceramide, and then, the GlcCer unit serves as a common coupling partner for the oligosaccharide donors [52]. This enzyme is also available in the ER and microsome [53].…”

Section: Structure and Functions Of Glucosylceramide Synthase And Glumentioning

confidence: 99%

“…P-gp has been also reported to prevent human AML cells from C8:ceramide-mediated apoptosis, and inhibition of P-gp resulted in the sensitization of the cells to apoptosis via C8:ceramide [54]. P-gp expression has been reported to be responsible for the development of resistance against the apoptotic effects of C6:ceramide on HeLa cells [52].…”

Section: Glucosylceramide Synthase In Drug Resistancementioning

confidence: 99%

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Yandım

Apohan

Baran

2012

Cancer Chemother Pharmacol

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Sphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDPglucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance.

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“…12,17 Using pgp-positive TF-1 cells, we have shown that pgp is present in the Golgi of AML cells, that glucosylceramide is a pgp substrate and that GCS activity is inhibited by the pgp inhibitors cyclosporin and GF120918. 18 These results indicate that pgp is involved in depleting cytosolic levels of glucosylceramide through its role as a lipid transporter, hence leading to increased GCS activity, decreased intracellular levels of ceramide and a drug-resistant phenotype. Similar findings have been made in breast cancer cells.…”

Section: Introductionmentioning

confidence: 88%

“…31 We believe that the mode of action of cyclosporin in this context results from inhibiting the pgp-dependent translocation of glucosylceramide (Figure 1), because cyclosporin only inhibits GCS activity in intact AML cells (membrane transporters operative) but not in a cell lysate (no transport function required). 18 Inhibition of GCS enhances intracellular levels of the proapoptotic mediator ceramide, which has a key role as a mediator of daunorubicin-induced apoptosis. PSC833 has a different effect, raising ceramide levels by stimulating de novo synthesis.…”

Section: P-glycoprotein (Pgp) In Amlmentioning

confidence: 99%

Strategies for overcoming p-glycoprotein-mediated drug resistance in acute myeloblastic leukaemia

Pallis

Russell

2004

Leukemia

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P-glycoprotein is implicated in the inhibition of ceramide-induced apoptosis in TF-1 acute myeloid leukemia cells by modulation of the glucosylceramide synthase pathway

Cited by 46 publications

References 60 publications

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

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

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Strategies for overcoming p-glycoprotein-mediated drug resistance in acute myeloblastic leukaemia

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