Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and IGF-independent mechanism.
Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is known to block IGF action and inhibit cell growth. IGFBP-3 is thought to act by sequestering free IGFs or, possibly, act via a novel IGF-independent mechanism. Supporting its role as a primary growth inhibitor, IGFBP-3 production has been shown to be increased by cell growth-inhibitory agents, such as transforming growth factor-beta (TGF-beta), and the tumor suppressor gene p53. In this paper, we demonstrate, for the first time, a novel function of IGFBP-3 as an apoptosis-inducing agent and show that this action is mediated through an IGF.IGF receptor-independent pathway. In the p53 negative prostate cancer cell line, PC-3, the addition of recombinant IGFBP-3 resulted in a dose-dependent induction of apoptosis. 125I-IGFBP-3 bound with high affinity to specific proteins in PC-3 cell lysates and plasma membrane preparations. These membrane-associated molecules may serve as receptors that mediate the direct effect of IGFBP-3 on apoptosis. In addition, in an IGF receptor-negative mouse fibroblast cell line, treatment with recombinant IGFBP-3 as well as transfection of the IGFBP-3 gene induced apoptosis, suggesting that neither IGFs nor IGF receptors are required for this action. Furthermore, treatment with TGF-beta1, a known apoptosis-inducing agent, resulted in the induction of IGFBP-3 expression 6-12 h before the onset of apoptosis. This effect of TGF-beta1 was prevented by co-treatment with IGFBP-3-neutralizing antibodies or IGFBP-3-specific antisense thiolated oligonucleotides. These findings suggest that IGFBP-3 induces apoptosis through a novel pathway independent of either p53 or the IGF.IGF receptor-mediated cell survival pathway and that IGFBP-3 mediates TGF-beta1 induced apoptosis in PC-3 cells.
Rajah
R
R
Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Valentinis
B
B
Cohen
P
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms; D017526:Receptor, IGF Type 1 / Q000502:physiology; D017527:Receptor, IGF Type 2 / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018972:Insulin-Like Growth Factor Binding Protein 3; D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1