Neuroblastoma cells in culture contain low levels of
cyclic AMP, a second messenger which plays a major role in neuronal maturation. In this study, human
neuroblastoma cells, SK-N-SH-SY5Y, were induced to differentiate by treatment with either
nerve growth factor (50 ng/ml),
retinoic acid (10 microM),
dibutyryl cyclic AMP (1 mM), or 12-O-tetradecanoylphorbol-13-acetate (0.1 microM), and the ability of several
neurotransmitters or
hormones to stimulate
adenylyl cyclase was tested. Although all four differentiation factors caused morphological changes towards a neuronal phenotype, only
retinoic acid dramatically enhanced
cyclic AMP accumulation, specifically upon stimulation with
prostaglandin E1 (
PGE1).
PGE2 was also active, but less potent, than
PGE1, whereas the other
cyclic AMP-stimulating agents tested were largely unaffected. Further, the rapid desensitization of the PGE1-cyclic
AMP response observed in control cells after 20 min of
PGE1 exposure did not occur in
retinoic acid-treated cells, and the EC50 values for
PGE1 were reduced from approximately 240 to 14 nM after
retinoic acid treatment. The increased sensitivity to
PGE was associated with an increase of high-affinity
PGE1 binding sites, whereas the Gs coupling
proteins and
adenylyl cyclase were not measurably affected. A similar enhancement of the PGE1-cyclic
AMP response by
retinoic acid was also observed in two additional human
neuroblastoma cell lines tested, Kelly and IMR-32, suggesting that up-regulation of the
prostaglandin response by
retinoic acid is common among
neuroblastoma cells.(ABSTRACT TRUNCATED AT 250 WORDS)