Insulin-like growth factor-II/mannose 6-phosphate receptor overexpression reduces growth of choriocarcinoma cells in vitro and in vivo.
The IGF-II/mannose-6 phosphate receptor (IGF-II/M6PR) interacts with multiple tumor growth factors, including IGF-II and latent TGFbeta1. The IGF-II/M6PR has been proposed to be a tumor growth suppressor, a hypothesis supported by our previous finding that decreased IGF-II/M6PR expression enhances tumor growth. In this study, we further demonstrate that IGF-II/M6PR overexpression, resulting from cDNA transfection of JEG-3 choriocarcinoma cells, leads to a decreased cellular growth rate in vitro and decreased tumor growth in nude mice. Examination of several IGF-II/M6PR ligands in receptor-overexpressing cells showed no change in endogenous IGF-II or secretion of procathepsins D and L but an increase in latent TGFbeta1 secretion and activation. Cells transfected with cDNA for a truncated, soluble form of the receptor, previously shown to inhibit IGF-II-stimulated DNA synthesis, displayed a very slow growth rate in vitro and in nude mice but showed no alteration in TGFbeta1 levels. This suggests that, in IGFII/M6PR-transfected cells, increased levels of soluble IGF-II/M6PR may play a role in growth inhibition. Overall, the findings in this study are consistent with the hypothesis that the IGF-II/M6PR suppresses tumor growth.
O'Gorman
David B
DB
Kolling Institute of Medical Research, University of Sydney and Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia.
Weiss
Jocelyn
J
Hettiaratchi
Anusha
A
Firth
Sue M
SM
Scott
Carolyn D
CD
D000818:Animals; D015152:Blotting, Northern; D002455:Cell Division; D002822:Choriocarcinoma / Q000473:pathology*; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000032:analysis; D017527:Receptor, IGF Type 2 / Q000097:blood / Q000235:genetics* / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2