A non-IGF binding mutant of IGFBP-3 modulates cell function in breast epithelial cells.
We demonstrated previously that IGFBP-3 alone had no effect on cell death, but dramatically modulated apoptosis in Hs578T IGF non-responsive cells. We investigated whether a non-IGF binding mutant of IGFBP-3 retained its intrinsic actions in this cell line, prior to investigating its actions in IGF-responsive cells (MCF-7 and MCF-10A). In the Hs578T cells, the ceramide analogue, C2-induced apoptosis, non-glycosylated, glycosylated or mutant IGFBP-3 alone had no effect but on co-incubation with C2, all forms of IGFBP-3 markedly accentuated triggered apoptosis. In MCF-7 cells, IGFBP-3 was unable to modulate C2-induced death. In the MCF-10A cells, IGFBP-3 acted as a potent survival factor. IGFBP-3 also affected cell growth in the MCF-10A cells (inhibiting at low doses but increasing growth at higher concentrations). These actions of IGFBP-3 in the MCF-10A cells were independent of IGF-1. IGFBP-3 has differential IGF-independent effects on cell death and growth in normal breast and breast cancer cells.
Perks
C M
CM
University Department of Surgery, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK. Claire.M.Perks@bris.ac.uk
McCaig
C
C
Clarke
J B
JB
Clemmons
D R
DR
Holly
J M P
JM
D017209:Apoptosis; D001940:Breast / Q000166:cytology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009154:Mutation; D013002:Somatomedins / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D018972:Insulin-Like Growth Factor Binding Protein 3; C064769:N-acetylsphingosine; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D013110:Sphingosine