Human melanoma cell invasion is inhibited in vitro by swainsonine and deoxymannojirimycin with a concomitant decrease in collagenase IV expression.
A 48 h pretreatment of two malignant and invasive human melanoma cell lines with either swainsonine (an inhibitor of Golgi alpha-mannosidase II) or deoxymannojirimycin (a Golgi alpha-mannosidase I inhibitor) resulted in a dose-dependent decrease in the cells' ability to invade a reconstituted basement membrane in vitro. This effect was reversible within 48 h of removing the drugs. Treatment with either drug resulted in both cell lines being more resistant to the cytotoxic effects of the lectin leukoagglutinin (PHA-L) and more sensitive to the lectin concanavalin A which indirectly indicated a change in the cell surface oligosaccharide composition and structure consistent with the known effects of these drugs on N-linked oligosaccharide processing. A 25-33% decrease was noted in the adhesion of treated cells to either a reconstituted basement membrane or human umbilical vein endothelial cell monolayer while no change was measured in the cells' proliferative rates. A correlative decrease was observed, however, in the expression of human type IV collagenase mRNA which was recovered within 48 h of removing the drugs. These results suggest that a correlation exists between the drug-induced changes in the cell surface oligosaccharide composition and structure with a concomitant decrease in the mRNA and secreted levels of type IV collagenase and the ability of these cells to invade.
Seftor
R E
RE
Department of Anatomy, University of Arizona College of Medicine, Tucson 85724.
Seftor
E A
EA
Grimes
W J
WJ
Liotta
L A
LA
Stetler-Stevenson
W G
WG
Welch
D R
DR
Hendrix
M J
MJ
D017485:1-Deoxynojirimycin; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003864:Depression, Chemical; D018093:Gelatinases; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006001:Glycoconjugates / Q000502:physiology; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D008361:Mannosidases / Q000037:antagonists & inhibitors; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D003012:Microbial Collagenase / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010434:Pepsin A / Q000096:biosynthesis*; D010835:Phytohemagglutinins; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017026:Swainsonine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D043323:alpha-Mannosidase
D006001:Glycoconjugates; D009363:Neoplasm Proteins; D010835:Phytohemagglutinins; D017485:1-Deoxynojirimycin; D008361:Mannosidases; D043323:alpha-Mannosidase; D010434:Pepsin A; D018093:Gelatinases; D003012:Microbial Collagenase; D005944:Glucosamine; D017026:Swainsonine