Tamoxifen retards glycosphingolipid metabolism in human cancer cells

Cabot, Myles C.; Giuliano, Armando E.; Volner, Alon; Han, Tian

doi:10.1016/0014-5793(96)00942-8

Cited by 78 publications

(67 citation statements)

References 33 publications

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“…Furthermore, Paclitaxel-dependent cytotoxicity is abrogated by blocking ceramide production with L-cycloserine, an inhibitor of ceramide synthesis (Mc Closkey et al, 1996;Mehta et al, 2000). Tamoxifen, a triphenylethylene antiestrogen, blocks the conversion of ceramide to glucosylceramide, thereby promoting an increase in cellular ceramide concentration (Cabot et al, 1996;Lavie et al, 1997). The synthetic retinoid, 4-(N-hydroxyphenyl) retinamide (4-HPR) increases the level of intracellular ceramide in drug-resistant neuroblastoma cell lines and the LNCaP prostate cancer cell line (Maurer et al, 1999).…”

Section: Ceramide and Cancermentioning

confidence: 99%

Recent advances in the immunobiology of ceramide

Pandey

Murphy

Agrawal

2007

Experimental and Molecular Pathology

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Ceramide, a sphingosine-based lipid molecule, has emerged as a key regulator of a wide spectrum of biological processes such as cellular differentiation, proliferation, apoptosis and senescence. Sphingomyelinase-dependent hydrolysis of sphingomyelin, and de novo synthesis involving the coordinated action of serinepalmitoyl transferase and ceramide synthase, are the two major pathways involved in ceramide synthesis. Clustering of plasma membrane rafts into ceramide enriched platforms serves as an important transmembrane signaling mechanism for cell surface receptors. Ceramides have been implicated in apoptosis, stress-signaling cascades as well as ion channels. There is accumulating evidence that targeted manipulation of ceramide metabolism pathway has immense therapeutic potential and may eventually prove to be a boon in the design of novel strategies and development of innovative treatments for diverse conditions including cardiovascular diseases, cancer and Alzheimer's disease. As yet uncharacterized natural ceramide analogs and novel inhibitors of ceramide metabolism might prove to be potent drugs. In this review, we discuss significant advances that continue to provide intriguing insights into the complex cellular and molecular mechanisms underlying ceramide-mediated signaling cascades.

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Section: Ceramide and Cancermentioning

confidence: 99%

Recent advances in the immunobiology of ceramide

Pandey

Murphy

Agrawal

2007

Experimental and Molecular Pathology

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“…In the well studied case of multidrug resistance (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)14), MDR cells are able to escape the drug-induced apoptotic death elicited in their sensitive counterparts by a rise in the cellular ceramide levels through two distinctive features. MDR cells express high levels of efflux pump proteins belonging to the ATP-binding cassette superfamily of membrane transport proteins, such as MDR1 and MRP.…”

Section: Effect Of Hpr On Ceramide Levels In A2780 Cellsmentioning

confidence: 99%

“…Interestingly, in tumor cell lines, resistance to chemotherapeutic treatments is often associated with an increased ability of the cell to glycosylate ceramide, as a consequence of a higher activity of glucosylceramide synthase (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). High levels of GlcCer 1 (6 -9, 11, 12) and of glucosylceramide synthase activity (5,8,9) and/or expression (8,9,11,12) were detected in a number of drug-resistant cancer cell lines and in specimens from cancer patients not responding to chemotherapy treatment (13).…”

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confidence: 99%

“…High levels of GlcCer 1 (6 -9, 11, 12) and of glucosylceramide synthase activity (5,8,9) and/or expression (8,9,11,12) were detected in a number of drug-resistant cancer cell lines and in specimens from cancer patients not responding to chemotherapy treatment (13). GlcCer accumulation results in the ability of drugresistant cells to scavenge ceramide, thus preventing ceramideinduced apoptotic death.…”

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confidence: 99%

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Altered Sphingolipid Metabolism inN-(4-Hydroxyphenyl)- retinamide-resistant A2780 Human Ovarian Carcinoma Cells

Prinetti

Basso

Appierto

et al. 2003

Journal of Biological Chemistry

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In the present work, we studied the effects of fenretinide (N-(4-hydroxyphenyl)retinamide (HPR)), a hydroxyphenyl derivative of all-trans-retinoic acid, on sphingolipid metabolism and expression in human ovarian carcinoma A2780 cells. A2780 cells, which are sensitive to a pharmacologically achievable HPR concentration, become 10-fold more resistant after exposure to increasing HPR concentrations. Our results showed that HPR was able to induce a dose-and time-dependent increase in cellular ceramide levels in sensitive but not in resistant cells. This form of resistance in A2780 cells was not accompanied by the overexpression of multidrug resistance-specific proteins MDR1 P-glycoprotein and multidrug resistance-associated protein, whose mRNA levels did not differ in sensitive and resistant A2780 cells. HPR-resistant cells were characterized by an overall altered sphingolipid metabolism. The overall content in glycosphingolipids was similar in both cell types, but the expression of specific glycosphingolipids was different. Specifically, our findings indicated that glucosylceramide levels were similar in sensitive and resistant cells, but resistant cells were characterized by a 6-fold lower expression of lactosylceramide levels and by a 6-fold higher expression of ganglioside levels than sensitive cells. The main gangliosides from resistant A2780 cells were identified as GM3 and GM2. The possible metabolic mechanisms leading to this difference were investigated. Interestingly, the mRNA levels of glucosylceramide and lactosylceramide synthases were similar in sensitive and resistant cells, whereas GM3 synthase mRNA level and GM3 synthase activity were remarkably higher in resistant cells.

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“…Second, Tam may in¯uence cell growth by modulating the activity of phospholipases and the activation of lipid signaling pathways (Kiss, 1994). Additionally, Tam was found to induce the expression of transforming growth factor-b (Knabbe et al, 1987), to inhibit calmodulin dependent cyclin AMP phosphodiesterases (Rowlands et al, 1990) and to retard the metabolism of glycosphingolipids (Cabot et al, 1996) in dierent cell types. Whether these signaling molecules are involved in Tam-induced growth inhibition has not been clearly demonstrated.…”

Section: Kip1mentioning

confidence: 99%

Tamoxifen induces p21WAF1 and p27KIP1 expression in estrogen receptor-negative lung cancer cells

Lee¹,

Chuang²,

Hung³

1999

Oncogene

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Tamoxifen (Tam), besides its action as an anti-estrogen, also inhibits cell proliferation of estrogen receptor (ER)-negative cancer cells by an unknown mechanism. In this study, we used ER-negative lung cancer cells to clarify such ER-independent inhibitory eect of Tam. We found that Tam induced G1 growth arrest in these cells. However, our results indicated that the expression of G1 cyclins (including D1, 2, 3 and E) was not regulated by Tam in these lung cancer cells. Additionally, the protein levels of G1 acting cyclin-dependent kinases (CDKs), CDK2, 4 and 6, was unaltered in Tam

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Tamoxifen retards glycosphingolipid metabolism in human cancer cells

Cited by 78 publications

References 33 publications

Recent advances in the immunobiology of ceramide

Recent advances in the immunobiology of ceramide

Altered Sphingolipid Metabolism inN-(4-Hydroxyphenyl)- retinamide-resistant A2780 Human Ovarian Carcinoma Cells

Tamoxifen induces p21WAF1 and p27KIP1 expression in estrogen receptor-negative lung cancer cells

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