N-butyldeoxynojirimycin inhibits murine melanoma cell ganglioside metabolism and delays tumor onset.
Aberrant ganglioside metabolism is linked to tumor progression. Since ganglioside depletion reduced tumorigenicity of MEB4 murine melanoma cells, we studied N-butyldeoxynojirimycin (NB-DNJ), an imino sugar administered orally to inhibit glucosylceramide (GlcCer) synthase in patients with glycosphingolipid storage diseases, for effects on MEB4 melanoma tumor cell ganglioside metabolism, cell biology, and tumorigenesis. Here we show that 50 microM NB-DNJ reduced MEB4 cell GlcCer synthase activity (by 70%), ganglioside synthesis (by 61%), and shedding (by 37%) while ceramide concentrations and cell viability were unaffected. Partial ganglioside depletion caused a delay in tumor onset but not in tumor incidence, possibly because of rapid (48 h) ganglioside recovery. The delay in tumor development by NB-DNJ treatment of MEB4 cells provides further support for the concept of tumor cell ganglioside metabolism as a therapeutic target in cancer.
Guerrera
Michael
M
Glycobiology Program, Center for Cancer and Transplantation Biology, Children's Research Institute, Children's National Medical Center, 111 Michigan Ave., N.W., Washington, DC 20010, USA.
Ladisch
Stephan
S
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005732:Gangliosides / Q000378:metabolism*; D005964:Glucosyltransferases / Q000187:drug effects* / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation
D002518:Ceramides; D004791:Enzyme Inhibitors; D005732:Gangliosides; D017485:1-Deoxynojirimycin; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase