3'-Azidothymidine significantly alters glycosphingolipid synthesis in melanoma cells and decreases the shedding of gangliosides.
In this report, we establish that 3'-azido-3'-deoxythymidine (AZT) treatment of melanoma cells greatly alters the pattern of glycosphingolipid biosynthesis. In SK-MEL-30 cells, synthesis of the gangliosides GM3 and GD3 was significantly inhibited (60% and 50% of control, respectively) and the production of their precursor, lactosylceramide, was stimulated by 2.5-fold. Control experiments established that phospholipid synthesis was not affected by AZT treatment, consistent with AZT treatment only affecting lipid biosynthetic reactions that involve glycosylation. Likely as a consequence of decreased rates of ganglioside synthesis, AZT treatment of SK-MEL-30 cells also significantly suppressed the amount of gangliosides shed from the membranes of these cells. Since shedding of gangliosides has been proposed to allow melanoma cells to avoid destruction by the immune system and alterations of glycosphingolipid levels are likely important for the malignant cell phenotype, these results may have important implications regarding the potential use of AZT or related glycosylation inhibitors as cancer chemotherapeutics.
Steet
R
R
Department of Chemistry and Biochemistry, University of Colorado, Boulder 80309-0215, USA.
Alizadeh
M
M
Melançon
P
P
Kuchta
R D
RD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005679:G(M3) Ganglioside / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005732:Gangliosides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006028:Glycosphingolipids / Q000096:biosynthesis*; D010743:Phospholipids / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005679:G(M3) Ganglioside; D005732:Gangliosides; D006028:Glycosphingolipids; D010743:Phospholipids; D015215:Zidovudine; C026226:ganglioside, GD3