Glycosphingolipids in Cellular Interaction, Differentiation, and Oncogenesis

Hakomori, Sen‐itiroh

doi:10.1007/978-1-4757-0396-2_4

Cited by 212 publications

(264 citation statements)

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“…These functions include adhesion, cellular growth and differentiation, apoptosis and surface antigens. [8][9][10]34,37 In addition, they can serve as a binding site for bacteria, viruses and toxins. 34,38 An increase in the concentration of glycosphingolipids on the cellular membrane of cancer cells leads to significant changes of the antigenic properties, including the formation of tumor-associated carbohydrate antigens, and a loss of adhesion, as well as increased motility enhancing invasion and metastasis.…”

Section: Galcer Inhibits Apoptosis and Interrupts Cellular Adhesionmentioning

confidence: 99%

“…1,2,4,5 Glycosphingolipids are known to be increased upon the surface of cancer cells and play an important role in inhibition of cellular adhesion and apoptosis. [6][7][8][9][10][11][12][13] There is currently little explanation for increased levels of glycosphingolipids within the cellular membrane of cancer cells, except one finding of transcriptional repression of the GALC gene in head and neck squamous cell carcinoma (HNSCC), and an increased utilization of ceramide to glycosylated forms in cancer cells stimulated by antineoplastic drugs. [14][15][16] Our article intends to illuminate the mechanisms of GALC suppression as well as other ways of GalCer accumulation and their impact on tumor pathology.…”

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confidence: 99%

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Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

Beier

Görögh

2005

Intl Journal of Cancer

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Galactosylcerebroside is known to be overexpressed upon the cellular surface of a variety of cancers. In squamous cell carcinomas of the head and neck, one explanation for galactosylcerebroside accumulation has been identified as a transcriptional repression of the galactocerebrosidase gene. Galactocerebrosidase is the enzyme responsible for degrading galactosylcerebroside to ceramide. Ceramide is an important apoptosis activator, whereas galactosylcerebroside functions as an inhibitor. A shift of the ceramide metabolism balance in favor of glycosylated forms has been identified as a mechanism of drug resistance for several antineoplastic agents. Our review elaborates on possible explanations for galactocerebrosidase suppression and on other explanations for increased glycosphingolipid concentration within cancer cell membranes. Furthermore, conjecturable influences of a repressed galactocerebrosidase expression on tumor biology are to be explained. The inhibiting transcription factors YY1 and AP2 have been identified as potential galactocerebrosidase gene suppressors. The resulting accumulation of galactosylcerebroside promotes a reduction of cellular adhesion and inhibits apoptosis, leading to increased cellular growth, migration and prolonged cell survival contributing to carcinogenesis. ' 2005 Wiley-Liss, Inc.

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Section: Galcer Inhibits Apoptosis and Interrupts Cellular Adhesionmentioning

confidence: 99%

mentioning

confidence: 99%

Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

Beier

Görögh

2005

Intl Journal of Cancer

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“…Glycosphingolipids (GSLs) 2 are eukaryotic lipids composed of a hydrophobic ceramide moiety crowned with a sugar headgroup (1)(2)(3). Located principally in the outer leaflet of the plasma membrane, they have diverse functions in cellular and organismal biology.…”

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confidence: 99%

Reconstitution of Glucosylceramide Flip-Flop across Endoplasmic Reticulum

Chalat

Menon

Turan

et al. 2012

Journal of Biological Chemistry

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Background: Lipid flip-flop, a key feature of many glycolipid biosynthetic pathways, requires as yet unidentified flippase proteins. Results: Glucosylceramide flips slowly across protein-free vesicles but rapidly across vesicles reconstituted with ER membrane proteins. Conclusion: Glucosylceramide flipping is facilitated by ATP-independent ER phospholipid flippases. Significance: Defining how glucosylceramide is transported across membranes is critical for understanding the glycosphingolipid biosynthetic pathway.

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“…It has been demonstrated, for example, that the blood group antigens A & B, which are cell surface glycoconjugates (Hakomori, 1981b), are lost in human malignant and premalignant lesions, and that the precursor H antigen accumulates (Dabelsteen & Pindborg, 1973;Dabelsteen et al, 1975;Dabelsteen et al, 1983; Kuhns & Primus, 1985). The biological significance of such changes in cell surface glycoconjugates is incompletely understood but it has been suggested that changes in cell surface glycoconjugates may disrupt normal processes such as proliferation (Hakomori, 1985), adhesion (Hakomori, 1981a;Okada et al, 1984) and contact inhibition of cell movement (Nicolson, 1974), resulting in disrupted growth control and cellular recognition -features characteristic of malignant neoplasia. What is not clear, however, is whether the changes in cell surface carbohydrates that occur in overt malignancies also act as reliable predictors of impending malignancy.…”

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confidence: 99%

Loss of epithelial cell surface carbohydrates during experimental oral carcinogenesis in the rat

Prime¹,

Rosser²,

Davies³

et al. 1987

Br J Cancer

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Cell surface glycoconjugates were investigated in a rat model of oral chemical carcinogenesis. The lectins Griffonia simplicifolia (GS-I-B4; specific for a-D-galactosyl end groups) and Ulex europeus (UEA-I; specific for a-L-fucosyl groups) were examined microspectrofluorimetrically in the oral epithelium of rats painted with the carcinogen 4-nitroquinoline N-oxide (4NQO) and compared with those treated with solvent alone. After labelling with GS-I-B4, the fluorescent intensity of the basal and parabasal epithelial cells was significantly less after 9 months of 4NQO treatment and in overt squamous cell carcinomas compared to controls. The fluorescent activity of the spinous epithelial cells in the non-invasive tissues treated with 4NQO and in the well differentiated (sites of keratin elaboration) malignant epithelium of squamous cell carcinomas was unchanged after labelling with UEA-I. UEA-I failed to stain undifferentiated (areas lacking keratin) malignant epithelium. The Cell surface carbohydrates change with malignant transformation (Nicolson, 1976;Hakomori, 1985). It has been demonstrated, for example, that the blood group antigens A & B, which are cell surface glycoconjugates (Hakomori, 1981b), are lost in human malignant and premalignant lesions, and that the precursor H antigen accumulates (Dabelsteen & Pindborg, 1973;Dabelsteen et al., 1975;Dabelsteen et al., 1983; Kuhns & Primus, 1985). The biological significance of such changes in cell surface glycoconjugates is incompletely understood but it has been suggested that changes in cell surface glycoconjugates may disrupt normal processes such as proliferation (Hakomori, 1985), adhesion (Hakomori, 1981a;Okada et al., 1984) and contact inhibition of cell movement (Nicolson, 1974), resulting in disrupted growth control and cellular recognition -features characteristic of malignant neoplasia. What is not clear, however, is whether the changes in cell surface carbohydrates that occur in overt malignancies also act as reliable predictors of impending malignancy.It appears that the acquisition of the malignant phenotype in human oral epithelial malignant lesions is associated with a diminished expression of certain lectin-labelled cell surface sugar residues (Dabelsteen & Mackenzie, 1978;Prime et al., 1985a). Recently, we described the topographical binding of the lectins Griffonia simplicifolia (GS-I-B4; specific for a-Dgalactosyl groups) and Ulex europeus (UEA-I; specific for a-L-fucosyl groups) in rat oral mucosa and demonstrated specificity of the labelling to basal/parabasal and spinous epithelial cells, respectively (Prime et al., 1986b). The lectins GS-I-B4 and UEA-I, therefore, can be used as markers of epithelial differentiation (Brabec et al., 1980) and this makes them ideal probes for the study of cell surface carbohydrate changes in carcinogenesis.Rodent tumours, comparable with human oral carcinomas (Prime et al., 1986a) can be induced by 4-nitroquinoline-Noxide (4NQO) (Wallenius & Lekholm, 1973). Since the tumours develop in all animals after a...

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Glycosphingolipids in Cellular Interaction, Differentiation, and Oncogenesis

Cited by 212 publications

References 214 publications

Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

Implications of galactocerebrosidase and galactosylcerebroside metabolism in cancer cells

Reconstitution of Glucosylceramide Flip-Flop across Endoplasmic Reticulum

Loss of epithelial cell surface carbohydrates during experimental oral carcinogenesis in the rat

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