Beta1,6-branched oligosaccharides regulate melanin content and motility in macrophage-melanoma fusion hybrids.
In previous studies, fusion of peritoneal macrophages or blood monocytes with mouse melanoma cells produced hybrids with upregulated expression of the glycosyltransferase beta1,6-N-acetylglucosaminyltransferase V (GnT-V) and its enzymatic product, beta1,6-branched oligosaccharides. This correlated with marked increases in motility, metastatic potential and, surprisingly, melanin content. This study was designed to establish direct roles for beta1,6-branched oligosaccharides in melanogenesis and motility. The levels of beta1,6-branched oligosaccharides were lowered by transfecting beta1,4-N-acetylglucosaminyltransferase III, a competitive inhibitor of GnT-V. beta1,4-N-acetylglucosaminyltransferase III transfection virtually eliminated melanin production and markedly decreased chemotactic motility. This implied that the metastatic and melanogenic phenotypes in hybrids were each upregulated by beta1,6-branched oligosaccharides. Although roles for beta1,6-branched oligosaccharides in motility and metastasis have been reported previously, this is the first study to directly implicate these structures in melanogenesis. Although drawn from experimental models, the findings might explain the well known hypermelanotic regions of human cutaneous malignant melanoma as hypermelanotic cutaneous malignant melanoma cells are rich in beta1,6-branched oligosaccharides. They might also explain why melanogenesis pathways differ between malignant and normal melanocytes as GnT-V is a myeloid-associated enzyme that is aberrantly expressed in melanoma cells but not in normal melanocytes.
Chakraborty
Ashok K
AK
Department of Dermatology and the Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8059, USA.
Pawelek
John
J
D000818:Animals; D002459:Cell Fusion; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D006822:Hybrid Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D008543:Melanins / Q000378:metabolism*; D008545:Melanoma / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008811:Mice, Inbred DBA; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D009844:Oligosaccharides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D008543:Melanins; D009844:Oligosaccharides; D012333:RNA, Messenger; D014442:Monophenol Monooxygenase; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase