IGFBP-3 sensitizes prostate cancer cells to interferon-gamma-induced apoptosis

Objective: Insulin-like growth factor binding protein-3 (IGFBP-3) has been shown to exhibit diverse biological actions, including IGF-independent effects on cell growth and cell death. Here we report that IGFBP-3 sensitizes prostate cancer cells to interferon-gamma (IFN-γ)-induced apoptosis and inhibition of cell proliferation. Design: The cell growth or cell death of prostate cells in response to the treatments of IGFBPs and/or IFN-γ was measured, and the signaling pathways mediating these actions assessed. Results: Cell proliferation was minimally affected when M12 prostate cancer cells were treated with exogenous IGFBP-3 (1-5 μg/ml), IGFBP-1 (1-5 μg/ml) or IFN-γ (20 U/ml). However, strong inhibition of cell growth and significant apoptosis were observed when M12 cells were co-treated with IGFBP-3 and IFN-γ, but not with IGFBP-1 and IFN-γ. These effects were IGF-independent and appear not to require intracellular localization of IGFBP-3, as similar results were obtained with mutants of IGFBP-3 that either could not bind IGF or has impaired ability to be internalized. Further analyses revealed that IGFBP-3, but not IGFBP-1, could significantly enhance the weak tyrosine phosphorylation of STAT1 induced by IFN-γ (20 U/ml) alone. The IGFBP-3-promoted apoptosis in the presence of IFN-γ could also be abrogated by blockade of the mTOR pathway with its pharmacological inhibitors, LY294002 or rapamycin. Conclusions: These results demonstrated that in a cancer cell line not responsive to exogenous IGFBP-3 alone, IGFBP-3 sensitized the cells to the anti-proliferative, proapoptotic actions of IFN-γ through an IGF-independent, STAT1- and mTOR-dependent mechanism.