Alterations in neuroblastoma ganglioside synthesis by induction of GD1b synthase by retinoic acid.
Recent findings link increased expression of the structurally complex 'b' pathway gangliosides GD1b, GT1b, GQ1b (CbG) to a favourable clinical and biological behaviour in human neuroblastoma (NB). Seeking a model to probe these observations, we evaluated four human NB cell lines. Very low CbG content (4-10%) in three of the four cell lines (LAN-5, LAN-1, SMS-KCNR) reflected the ganglioside pattern observed in the most aggressive NB tumours. Pharmacological alterations of complex ganglioside synthesis in vitro by a 5-7 day exposure to 5-10 microM retinoic acid, which is employed in maintenance therapy of disseminated NB, included markedly increased (i) relative expression of CbG (6.6+/-2.0-fold increase, P=0.037), (ii) relative expression of the analogous 'a' pathway gangliosides, termed CaG (6.4+/-1.4-fold increase in GM1a and GD1a; P=0.010), and (iii) total cellular ganglioside content (2.0-6.3-fold), which in turn amplified the accumulation of structurally complex gangliosides. Substantial increases (2.7-2.9-fold) in the activity of GD1b/GM1a synthase (beta-1,3-galactosyltransferase), which initiates the synthesis of CbG and CaG, accompanied the all-trans retinoic acid (ATRA)-induced ganglioside changes. Thus, increased CbG synthesis in NB cell lines is attributable to a specific effect of ATRA, namely induction of GD1b/GM1a synthase activity. Since the shift towards higher expression of CbG and CaG during retinoic acid-induced cellular differentiation reflects a ganglioside pattern found in clinically less-aggressive tumours, our studies suggest that complex gangliosides may play a role in the biological and clinical behaviour of NB.
Hettmer
S
S
Glycobiology Program, Center for Cancer and Immunology Research, Children's National Medical Center, and Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington DC 20010, USA.
McCarter
R
R
Ladisch
S
S
Kaucic
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation; D005700:Galactosyltransferases / Q000378:metabolism*; D005732:Gangliosides / Q000378:metabolism*; D005964:Glucosyltransferases / Q000096:biosynthesis*; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005732:Gangliosides; C033851:ganglioside, GD1b; D014212:Tretinoin; D005700:Galactosyltransferases; D005964:Glucosyltransferases