Insulin-like growth factor binding protein-3 induces apoptosis in MCF7 breast cancer cells.
Insulin-like growth factors (IGFs) are known to have potent antiapoptotic activity. The antiestrogen ICI 182,780 (ICI) is a potent inhibitor of MCF7 human breast cancer cell growth and has recently been reported to act as an antiproliferative agent in part via upregulation of expression of insulin-like growth factor binding proteins (IGFBPs) -3 and -5, which attenuate the bioactivity of IGFs in many experimental systems. We show here that ICI and IGFBP-3 induce apoptosis in MCF7 cells. Treatment of MCF7 cells with 10 nM ICI or 36 nM recombinant human IGFBP. 3 for 72 hours increased apoptosis approximately 3.5-fold relative to control as quantitated by a cell death ELISA which measures DNA fragmentation. Long R3 IGF-I, an IGF-I analogue with greatly reduced affinity for IGFBPs yet similar affinity for IGF-I receptors, was a more potent inhibitor of IGFBP-3-induced and ICI-induced apoptosis than IGF-I. These results suggest that IGFBP-3 enhances apoptosis by reducing bioavailability of ligands for the IGF-I receptor and suggest that modulation of IGFBP-3 expression by ICI contributes to apoptosis induced by this compound. More generally, the data suggest that IGFBPs are regulators of apoptosis.
Nickerson
T
T
Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada.
Huynh
H
H
Pollak
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007700:Kinetics; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D000077267:Fulvestrant; D004958:Estradiol; D007334:Insulin-Like Growth Factor I