Glycosynaptic microdomains controlling tumor cell phenotype through alteration of cell growth, adhesion, and motility

AbstractGlycosphingolipids (GSLs) GM3 (NeuAcα3Galβ4Glcβ1Cer) and GM2 (GalNAcβ4[NeuAcα3]Galβ4Glcβ1Cer) inhibit (i) cell growth through inhibition of tyrosine kinase associated with growth factor receptor (GFR), (ii) cell adhesion/motility through inhibition of integrin-dependent signaling via Src kinases, or (iii) both cell growth and motility by blocking “cross-talk” between integrins and GFRs. These inhibitory effects are enhanced when GM3 or GM2 are in complex with specific tetraspanins (TSPs) (CD9, CD81, CD82). Processes (i)–(iii) occur through specific organization of GSLs with key molecules (TSPs, caveolins, GFRs, integrins) in the glycosynaptic microdomain. Some of these processes are shared with epithelial–mesenchymal transition induced by TGFβ or under hypoxia, particularly that associated with cancer progression

Evaluation of ricin A chain-containing immunotoxins directed against glycolipid and glycoprotein on mouse lymphoma cells.

Immunotoxins composed of monoclonal antibodies (mAbs) and various toxins have been developed for the treatment of malignancies. We investigated the efficacy of three ricin toxin A-chain (RTA)-containing immunotoxins (ITs) conjugated from mAbs which recognize glycolipid asialo-GM2 and glycoprotein H-2d. These ITs retained the same immunoreactivity with mAbs. We evaluated the cytotoxicity of these ITs against mouse lymphoma cells L5178Y variants showing high (AA12,CC9) and low (27AV) expression of asialo-GM2. Anti-H-2d-RTA IT had the strongest cytotoxicity for all cell lines. Anti-asialo-GM2 (IgM)-RTA IT had stronger cytotoxicity than anti-asialo-GM2 (IgG3)-RTA IT. Anti-asialo-GM2-RTA ITs had different cytotoxicity against AA12 and CC9 cells. The establishment of appropriate anti-glycolipid mAbs may lead to effective immunotargeting therapy.</p

A monoclonal antibody directed to N-acetylneuraminosyl-alpha 2 leads to 6-galactosyl residue in gangliosides and glycoproteins

This research was originally published in the Journal of Biological Chemistry. S Hakomori, C M Patterson, E Nudelman and K Sekiguchi. A monoclonal antibody directed to N-acetylneuraminosyl-alpha 2 leads to 6-galactosyl residue in gangliosides and glycoproteins. J. Biol. Chem. 1983; 258: 11819-11822 © the American Society for Biochemistry and Molecular Biolog

Phenotypic changes in 3T3 cells associated with the change of sphingolipid synthesis by a ceramide analog, 2-decanoylamino-3-morpholino-1-phenylpropanol (compound RV538)

A culture of BALB/c 3T3 cells grown in the presence of 40 [mu]M of the ceramide analog compound RV538 (2-decanoylamino-3-morpholino-1-phenylpropanol) for several passages caused a substantial decrease in the level of all glycosphingolipids and an accumulation of ceramide and sphingomyelin. Associated with these chemical changes of sphingolipid composition and metabolism, the following phenotypic changes were observed: (i) loss of the cobblestone appearance at cell density saturation and development of fibroblastic appearance with partial overlapping of cells; (ii) reduction of cell growth rate; (iii) enhanced production of lactic acid; (iv) enhanced rate of glucose transport; and (v) higher incidence of large colony formation with infiltrating appearance in soft agar. Cell morphology changes, lactate pruduction, and enhanced sugar uptake were reversed by co-culturing cells with gangliosides, particularly trisialogangliosides. Thus, these phenotypic changes mimicking those of oncogenically transformed cells are closely related to the blocked synthesis of glycolipids in these cells, whereas other changes may be caused by an accumulation of ceramide and sphingomyelin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27183/1/0000186.pd

Domain structure of human plasma fibronectin : Differences and similarities between human and hamster fibronectins

This research was originally published in the Journal of Biological Chemistry. Kiyotoshi Sekiguchi and Sen-itiroh Hakomori. Domain structure of human plasma fibronectin : Differences and similarities between human and hamster fibronectins. J. Biol. Chem. 1983; 258: 3967-3973 © the American Society for Biochemistry and Molecular Biolog