Alterations in neuroblastoma ganglioside synthesis by induction of GD1b synthase by retinoic acid.

Abstract

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 μM 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 (β-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.