title: Effects of a non-IGF binding mutant of IGFBP-5 on cell death in human breast cancer cells.
abstract: We have demonstrated previously that IGFBP-5 alone had no effect on cell death but modulated ceramide-induced apoptosis in Hs578T IGF non-responsive cells. To investigate if IGFBP-5 maintains its intrinsic ability to modulate apoptosis in IGF-responsive cells, we used a non-IGF binding mutant of IGFBP-5. In Hs578T cells, non-glycosylated, glycosylated or mutant IGFBP-5 alone each had no effect on cell death, whereas all forms inhibited ceramide-induced apoptosis. In IGF-responsive MCF-7 cells, each wild type form reduced ceramide-induced cell death but mutant IGFBP-5 was without effect. In the presence of mutant IGFBP-5, however, IGF-I no longer conferred survival and in the presence of wild type IGFBP-5, long R3 IGF-I was also unable to confer survival. In summary, all forms of IGFBP-5 modulated ceramide-induced apoptosis in Hs578T cells. In MCF-7 cells, IGF-I-induced survival could be facilitated by IGFBP-5, but also blocked by IGFBP-5 if association with IGFBP-5 was prevented.
authors.affiliation: University Division of Surgery, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK. Claire.M.Perks@bris.ac.uk
authors.forename: C M
authors.initials: CM
authors.lastname: Perks
authors.forename: C
authors.initials: C
authors.lastname: McCaig
authors.forename: J B
authors.initials: JB
authors.lastname: Clarke
authors.forename: D R
authors.initials: DR
authors.lastname: Clemmons
authors.forename: J M P
authors.initials: JM
authors.lastname: Holly
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics* / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives* / Q000494:pharmacology; D009154:Mutation; D013002:Somatomedins / Q000378:metabolism / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D018975:Insulin-Like Growth Factor Binding Protein 5; C064769:N-acetylsphingosine; D013002:Somatomedins; C085700:long R(3)-insulin-like growth factor-I; D007334:Insulin-Like Growth Factor I; D013110:Sphingosine