Soluble insulin-like growth factor II/mannose 6-phosphate receptor inhibits DNA synthesis in insulin-like growth factor II sensitive cells

J Cell Physiol. 2000 Jan;182(1):62-8. doi: 10.1002/(SICI)1097-4652(200001)182:1<62::AID-JCP7>3.0.CO;2-X.


The soluble form of the insulin-like growth factor II (IGF-II)/mannose 6-P (IGF-II/M6P) receptor is released by cells in culture and circulates in the serum. It retains its ability to bind IGF-II and blocks IGF-II-stimulated DNA synthesis in isolated rat hepatocytes. Because these cells are not normally stimulated to divide by IGF-II in vivo, the effect of soluble IGF-II/M6P receptor on DNA synthesis has been further investigated in two cell lines sensitive to IGF-II; mouse 3T3(A31) fibroblasts, stimulated by low levels of IGF-II following priming by epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) and Buffalo rat liver (BRL) cells, which secrete IGF-II and proliferate in the absence of exogenous growth factors. Soluble IGF-II/M6P receptor (0.2-2.0 microgram/ml) purified from a rat hepatoma cell line inhibited DNA synthesis (determined by dThd incorporation) in both cell lines. Basal DNA synthesis was very low in serum-free 3T3 cells, but high in serum-free BRL cells, possibly as a result of autocrine IGF-II production. The inhibitory effect was reversible in cells preincubated with soluble receptor prior to incubation with growth factors and could also be overcome by excess IGF-II. Soluble receptor was more potent in IGF-II-stimulated 3T3 cells and serum-free BRL cells than in BRL cells incubated with serum. Mean inhibition by four preparations of soluble receptor (1 microgram/ml) was 34.7% +/- 4.4% in BRL cells stimulated with fetal calf serum (FCS) (5%) compared to 54.8% +/- 4.2% in serum-free BRL cells (P = 0.05) and 60.6% +/- 6.5% (P = 0.02) in 3T3 cells stimulated by PDGF, EGF, and IGF-II. Soluble receptor had no effect on DNA synthesis in 3T3 cells stimulated with IGF-I. These results demonstrate that soluble receptor, at physiological concentrations, can block proliferation of cells by IGF-II and could therefore play a role in blocking tumor growth mediated by IGF-II.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cell Line
  • Culture Media, Serum-Free
  • DNA / biosynthesis*
  • DNA / metabolism
  • Dose-Response Relationship, Drug
  • Epidermal Growth Factor / pharmacology
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor II / pharmacology*
  • Liver / cytology
  • Liver / drug effects
  • Liver / metabolism
  • Mice
  • Platelet-Derived Growth Factor / pharmacology
  • Rats
  • Receptor, IGF Type 2 / antagonists & inhibitors
  • Receptor, IGF Type 2 / physiology*
  • Solubility
  • Thymidine / metabolism
  • Time Factors


  • Culture Media, Serum-Free
  • Platelet-Derived Growth Factor
  • Receptor, IGF Type 2
  • Epidermal Growth Factor
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • DNA
  • Thymidine