Inhibition of lectin-mediated ovarian tumor cell adhesion by sugar analogs.
Adhesion of A-121 human ovarian carcinoma cells to extracellular matrix is partly mediated via interaction between galaptin, an endogenous beta-galactoside-binding lectin present in extracellular matrix, and specific cell surface carbohydrate receptors identified as lysosomal associated membrane proteins, lamp-1 and lamp-2. In this study, we report that adhesion of human ovarian carcinoma cells to polystyrene plates coated with polymerized human splenic galaptin can be inhibited by polyclonal antibodies raised against lamp-1 and lamp-2 molecules and by pretreatment of A-121 human ovarian carcinoma cells with glucosamine analogs: 2-acetamido-1,4,6-tri-O-acetyl-3- deoxy-3-fluoro-alpha-D-glucopyranose (3-F-GlcNAc) and 2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-alpha-D-glucopyranose (4-F-GlcNAc). A 48-h exposure of A-121 cells to individual sugar analogs, or to a combination of the two, resulted in a concentration-dependent inhibition of cellular attachment to polymerized galaptin. Both drugs inhibited glycoprotein biosynthesis as measured by cellular incorporation of labeled [3H]glucosamine and [3H]fucose with negligible effects on [3H]thymidine and [3H]leucine incorporation and cell growth. As a result of drug action on glycoprotein biosynthesis, an alteration in the structure of the galaptin receptor was noted by indirect immunofluorescence and Western blot analysis. Moreover, probing gels of cell extracts with anti-lamp antibodies or Datura stramonium lectin demonstrated significant changes in the reactivity and pattern of glycoprotein staining, suggesting an effect of sugar analogs on the glycosylation of various cellular receptor molecules. The greatest change was observed when tumor cells were exposed to a combination of the two sugar analogs. These studies suggest that specific endogenous lectins and their surface receptors play a role in tumor cell adhesion and perhaps metastasis and may serve as suitable targets for therapeutic exploitation.
Woynarowska
B
B
Department of Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263.
Skrincosky
D M
DM
Haag
A
A
Sharma
M
M
Matta
K
K
Bernacki
R J
RJ
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D013286:Datura stramonium; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D037483:Galectin 1; D006388:Hemagglutinins / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D037102:Lectins / Q000494:pharmacology / Q000502:physiology*; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology; D010051:Ovarian Neoplasms / Q000473:pathology / Q000503:physiopathology*; D037121:Plant Lectins; D010946:Plants, Medicinal; D010947:Plants, Toxic; D013154:Spleen; D014407:Tumor Cells, Cultured
D000906:Antibodies; D015703:Antigens, CD; C041384:Datura stramonium lectin; D037483:Galectin 1; D006388:Hemagglutinins; D037102:Lectins; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D037121:Plant Lectins; C089178:2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoroglucopyranose; C080445:2-acetamido-1,4,6-tri-O-acetyl-2,3-dideoxy-3-fluoroglucopyranose; D000117:Acetylglucosamine