Insulin-like growth factor-1 and dibutyryl CAMP induce differentiation and decrease opioid receptor binding activity...

The effects of fibroblast growth factor (FGF), insulin, insulin-like growth factor-1 (IGF-1), and dibutyryl cAMP (Bt(2)cAMP) on cell proliferation and differentiation, opioid receptor binding activity, and expression of fos, myc, and ras proto-oncogenes were studied in N4TG1 neuroblastoma cells. IGF-1 and insulin increased thymidine incorporation and cell number, but Bt(2)cAMP inhibited incorporation and FGF did not change thymidine incorporation after 24 h of treatment. Bt(2)cAMP profoundly extended and IGF-1 slightly extended neurite-like processes, a morphologic marker of neuronal differentiation. A combination of IGF-1 and Bt(2)cAMP potentiated neurite process extension. Thus, IGF-1 could induce both proliferation and differentiation of N4TG1 neuroblastoma cells. FGF did not cause neurite extension. N4TG1 neuroblastoma cells have a high density of alpha-opioid receptors. IGF-1 and Bt(2)cAMP, but not FGF and other growth factors, decreased delta-opioid receptor binding activity with a reduced B(max) value and a normal apparent K(d) value. Using Northern blot and hybridization, both acidic and basic FGF elicited stimulatory effects on fos expression. Cycloheximide (CHX), a protein synthesis inhibitor, potentiated and prolonged the effect of FGF on fos expression. However, FGF had no effect on myc or ras expression. Neither IGF-1 nor Bt(2)cAMP significantly changed fos, myc, or ras expression. The results suggest that fos, myc, or ras proto-oncogene expression is independent from or insufficient for IGF-1-induced and Bt(2)cAMP-induced differentiation and regulation of opioid receptor synthesis in N4TG 1 neuroblastoma cells.