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 mM retinoic acid, which is employed in maintenance therapy of disseminated NB, included markedly increased (i) relative expression of CbG (6.672.0-fold increase, P ¼ 0.037), (ii) relative expression of the analogous 'a' pathway gangliosides, termed CaG (6.471.4-fold increase in GM1a and GD1a; P ¼ 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 (b-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.

Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling, ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma cells

“…These data confirm the higher potency of the more defined extract of PAC-1A achieved with the current isolation protocol when compared to our previous study including SMSKCNR (15). SMS-KCNR cells exhibit a uniform phenotype with small, round N-type cells that have short neuritic processes (34). This cell line was chosen as a model for mechanistic experiments in the current report since they display MYCN amplification, express caspase-8 (35) and apoptosis can be mediated through the intrinsic as well as extrinsic pathway (36).…”

Comparative Proteomic Expression Profile in All-trans Retinoic Acid Differentiated Neuroblastoma Cell Line

“…We used the human LAN-5 NB cell line amplified for the oncogene N-MYC and responsive to ATRA treatment, 37,38 and monitored the cytosolic and nuclear protein expression in those cells at the early phase of ATRA differentiation. We used 5 µM ATRA, according to the known pharmacological doses used in phase I trials of RA administrated to NB patients.…”

Selection of novel peptide mimics of the GD2 ganglioside from a constrained phage-displayed peptide library

“…With reference to a vast number of research data, gangliosides have been related to tumorigenesis (3). An alteration in the ganglioside expression pattern has been linked to biological phenotype and clinical behavior that can be used to predict the prognosis of neuroblastoma patients (4,5). As for the GD2 ganglioside, high circulating levels of the tumor carbohydrate antigen were strongly related to more rapid disease progression and lower survival rates of advanced risk neuroblastoma patients (6).…”