IGF-binding protein-3-induced growth inhibition and apoptosis do not require cell surface binding and nuclear translocation in human breast cancer cells.
IGF-binding protein-3 (IGFBP-3) has both antiproliferative and proapoptotic effects on the growth of human breast cancer cells in vitro. However, the mechanisms governing these effects are not well understood. IGFBP-3 has been shown to associate with the cell surface through carboxyl-terminal residues. This suggests that it may interact with a specific cell surface receptor, although a signaling receptor for IGFBP-3 has not yet been fully characterized. IGFBP-3 also translocates to the nucleus and has been shown to interact with the nuclear RXRalpha, with evidence that this interaction may mediate its growth inhibitory and proapoptotic effects. Here we demonstrate that a mutant form of IGFBP-3 that has reduced cell surface binding and does not translocate to the nucleus is still growth inhibitory, elicits a potent G(1) cell cycle arrest, and induces apoptosis via modulation of Bcl-2 family members in human breast cancer cells. This suggests the existence of multiple pathways by which IGFBP-3 elicits its growth effects.
Butt
Alison J
AJ
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. abutt@med.usyd.edu.au
Fraley
Kristie A
KA
Firth
Sue M
SM
Baxter
Robert C
RC
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics*; D017077:Culture Media, Conditioned; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D006131:Growth Inhibitors; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000235:genetics*; D013936:Thymidine / Q000378:metabolism; D014162:Transfection; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D017077:Culture Media, Conditioned; D006131:Growth Inhibitors; D018972:Insulin-Like Growth Factor Binding Protein 3; D011956:Receptors, Cell Surface; D020169:Caspases; D013936:Thymidine