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Insulin-like Growth Factor Binding Protein-3 Mediates Tumor Necrosis Factor--induced Apoptosis: Role of Bcl-2 Phosphorylation¹

Department of Pediatrics, Mattel Children’s Hospital at UCLA, Los Angeles, California 90095

The insulin-like growth factor (IGF)-independent effects ofinsulin-like growth factor binding protein-3 (IGFBP-3) to effect cellular apoptosis have now been described in various cellular systems. IGFBP-3 mediates transforming growth factor-ß-induced apoptosis. Other growth-inhibitory and apoptosis-inducing agents such as tumor necrosis factor- (TNF-) and the tumor suppressor gene p53 also induce IGFBP-3. In this report, we demonstrate the role of IGFBP-3 as a mediator of apoptosis induced by TNF- and elucidate the process involved in its signaling mechanism. Treatment of PC-3 cells with TNF- resulted in the induction of IGFBP-3 expression in a dose- and time-dependent fashion and also induced apoptosis. TNF--induced apoptosis was prevented by cotreatment with IGFBP-3 neutralizing antibodies or IGFBP-3-specific antisense thiolated oligonucleotides. Both IGFBP-3 and TNF- treatment increased the levels of the inactive, serine phosphorylated form of the survival protein Bcl-2. The effect of TNF- on Bcl-2 serine phosphorylation was blocked by IGFBP-3 antisense oligomers. These findings confirm that IGFBP-3 is essential for TNF--induced apoptosis in PC-3 cells and that this IGFBP-3 effect includes the inactivation of Bcl-2 through serine phosphorylation.

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