Interference with O-glycosylation in RMA lymphoma cells leads to a reduced in vivo growth of the tumor.
Carbohydrate processing in cancer cells can influence the growth, metastatic potential, vascularization and immune recognition of such cells. Interference with N-glycosylation has been shown both to reduce the membrane expression of MHC class I and to increase the in vitro sensitivity of tumor cells to NK cell killing. We investigated the effect of O-glycosylation inhibition on the in vivo growth, phenotype and NK sensitivity of RMA lymphoma cells using benzyl N-acetyl-alpha-D-galactosamide (BAG). BAG-treated cells were found to have a strongly reduced local growth potential in vivo. However, inhibition of O-glycosylation caused this effect without any significant downregulation of MHC-I and increase in sensitivity to NK killing as seen after inhibition of N-glycosylation using Castanospermine. BAG treatment of RMA cells resulted in the removal of larger O-linked glycans and a high expression of the T-antigen (GalGalNAc), a target for natural antibodies (NAs) induced by the gastrointestinal bacterial flora. Whether the loss of larger O-linked glycans, and associated functions, or of biological effects of NA contributed to the antitumor effect remains to be established. The results support the idea that inhibitors of O- as well as N-linked glycosylation may be useful for the treatment of cancer, given that they can be specifically targeted to the tumor tissue.
Chen
Liying
L
Microbiology and Tumor Biology Center (MTC), Karolinska Institute, Stockholm, Sweden. Liying.Chen@mtc.ki.se
Sundbäck
Jonas
J
Olofsson
Sigvard
S
Jondal
Mikael
M
D000116:Acetylgalactosamine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001593:Benzyl Compounds / Q000378:metabolism; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors*; D006031:Glycosylation; D006801:Humans; D007212:Indolizines / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014407:Tumor Cells, Cultured; D054836:Indolizidines
D000116:Acetylgalactosamine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001593:Benzyl Compounds; D004791:Enzyme Inhibitors; D005962:Glucosylceramidase; D007212:Indolizines; C080739:benzyl-alpha-N-acetylgalactosamine; C037806:castanospermine; D054836:Indolizidines